Increased Plasma Ferritin Concentration and Low-Grade Inflammation—A Mendelian Randomization Study

Abstract BACKGROUND It is unknown why increased plasma ferritin concentration predicts all-cause mortality. As low-grade inflammation and increased plasma ferritin concentration are associated with all-cause mortality, we hypothesized that increased plasma ferritin concentration is genetically associated with low-grade inflammation. METHODS We investigated whether increased plasma ferritin concentration is associated with low-grade inflammation [i.e., increased concentrations of C-reactive protein (CRP) and complement component 3 (C3)] in 62537 individuals from the Danish general population. We also applied a Mendelian randomization approach, using the hemochromatosis genotype C282Y/C282Y as an instrument for increased plasma ferritin concentration, to assess causality. RESULTS For a doubling in plasma ferritin concentration, the odds ratio (95% CI) for CRP ≥2 vs <2 mg/L was 1.12 (1.09–1.16), with a corresponding genetic estimate for C282Y/C282Y of 1.03 (1.01–1.06). For a doubling in plasma ferritin concentration, odds ratio (95% CI) for complement C3 >1.04 vs ≤1.04 g/L was 1.28 (1.21–1.35), and the corresponding genetic estimate for C282Y/C282Y was 1.06 (1.03–1.12). Mediation analyses showed that 74% (95% CI, 24–123) of the association of C282Y/C282Y with risk of increased CRP and 56% (17%–96%) of the association of C282Y/C282Y with risk of increased complement C3 were mediated through plasma ferritin concentration. CONCLUSIONS Increased plasma ferritin concentration as a marker of increased iron concentration is associated observationally and genetically with low-grade inflammation, possibly indicating a causal relationship from increased ferritin to inflammation. However, as HFE may also play an immunological role indicating pleiotropy and as incomplete penetrance of C282Y/C282Y indicates buffering mechanisms, these weaknesses in the study design could bias the genetic estimates.

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Cancer Related Anemia: An Integrated Multitarget Approach and Lifestyle Interventions

Nutrients ◽

10.3390/nu13020482 ◽

2021 ◽

Vol 13 (2) ◽

pp. 482

Author(s):

Valentina Natalucci ◽

Edy Virgili ◽

Federica Calcagnoli ◽

Giacomo Valli ◽

Deborah Agostini ◽

...

Keyword(s):

Iron Homeostasis ◽

Iron Concentration ◽

Transferrin Saturation ◽

Intravenous Iron ◽

Complex Problem ◽

Low Grade ◽

Inflammatory Status ◽

Line Of Therapy ◽

Cancer Related Anemia ◽

Low Grade Inflammation

Cancer is often accompanied by worsening of the patient’s iron profile, and the resulting anemia could be a factor that negatively impacts antineoplastic treatment efficacy and patient survival. The first line of therapy is usually based on oral or intravenous iron supplementation; however, many patients remain anemic and do not respond. The key might lie in the pathogenesis of the anemia itself. Cancer-related anemia (CRA) is characterized by a decreased circulating serum iron concentration and transferrin saturation despite ample iron stores, pointing to a more complex problem related to iron homeostatic regulation and additional factors such as chronic inflammatory status. This review explores our current understanding of iron homeostasis in cancer, shedding light on the modulatory role of hepcidin in intestinal iron absorption, iron recycling, mobilization from liver deposits, and inducible regulators by infections and inflammation. The underlying relationship between CRA and systemic low-grade inflammation will be discussed, and an integrated multitarget approach based on nutrition and exercise to improve iron utilization by reducing low-grade inflammation, modulating the immune response, and supporting antioxidant mechanisms will also be proposed. Indeed, a Mediterranean-based diet, nutritional supplements and exercise are suggested as potential individualized strategies and as a complementary approach to conventional CRA therapy.

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Low-grade inflammation as a risk factor for cardiovascular events and all-cause mortality in patients with type 2 diabetes

Cardiovascular Diabetology ◽

10.1186/s12933-021-01409-0 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Shahnam Sharif ◽

Y. Van der Graaf ◽

M. J. Cramer ◽

L. J. Kapelle ◽

G. J. de Borst ◽

...

Keyword(s):

Myocardial Infarction ◽

Type 2 Diabetes ◽

Cardiovascular Events ◽

Low Grade ◽

All Cause Mortality ◽

High Risk Type ◽

Hs Crp ◽

Low Grade Inflammation ◽

Diabetes Patients

Abstract Background Type 2 diabetes is a condition associated with a state of low-grade inflammation caused by adipose tissue dysfunction and insulin resistance. High sensitive-CRP (hs-CRP) is a marker for systemic low-grade inflammation and higher plasma levels have been associated with cardiovascular events in various populations. The aim of the current study is to evaluate the relation between hs-CRP and incident cardiovascular events and all-cause mortality in high-risk type 2 diabetes patients. Methods Prospective cohort study of 1679 type 2 diabetes patients included in the Second Manifestations of ARTerial disease (SMART). Cox proportional hazard models were used to evaluate the risk of hs-CRP on cardiovascular events (composite of myocardial infarction, stroke and vascular mortality) and all-cause mortality. Hs-CRP was log-transformed for continuous analyses. Findings were adjusted for age, sex, BMI, current smoking and alcohol use, non-HDL-cholesterol and micro-albuminuria. Results 307 new cardiovascular events and 343 deaths occurred during a median follow-up of 7.8 years (IQR 4.2–11.1). A one unit increase in log(hs-CRP) was related to an increased vascular- and all-cause mortality risk (HR 1.21, 95% CI 1.01–1.46 and HR 1.26, 95% CI 1.10–1.45 respectively). No relation was found between log(hs-CRP) and myocardial infarction or stroke. The relations were similar in patients with and without previous vascular disease. Conclusion Low grade inflammation, as measured by hs-CRP, is an independent risk factor for vascular- and all-cause mortality but not for cardiovascular events in high-risk type 2 diabetes patients. Chronic low-grade inflammation may be a treatment target to lower residual cardiovascular risk in type 2 diabetes patients.

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Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study

Frontiers in Immunology ◽

10.3389/fimmu.2021.720876 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shucheng Si ◽

Jiqing Li ◽

Marlvin Anemey Tewara ◽

Fuzhong Xue

Keyword(s):

Mendelian Randomization ◽

Neurological Diseases ◽

Bipolar Disorders ◽

Electrolyte Imbalance ◽

Low Grade ◽

Uk Biobank ◽

Anemia Of Chronic Disease ◽

The Uk ◽

Genetically Determined ◽

Low Grade Inflammation

BackgroundC-reactive protein (CRP) has been used as a biomarker of chronic low-grade inflammation in observational studies. We aimed to determine whether genetically determined CRP was associated with hundreds of human phenotypes to guide anti-inflammatory interventions.MethodsWe used individual data from the UK Biobank to perform a phenome-wide two-stage least squares (2SLS) Mendelian randomization (MR) analysis for CRP with 879 diseases. Summary-level data from the FinnGen consortium were utilized to perform phenome-wide two-sample MR analysis on 821 phenotypes. Systematic two-sample MR methods included MR-IVW, MR-WME, MR-Mod, and MR-PRESSO as sensitivity analyses combined with multivariable MR to identify robust associations. Genetic correlation analysis was applied to identify shared genetic risks.ResultsWe found genetically determined CRP was robustly associated with 15 diseases in the UK Biobank and 11 diseases in the FinnGen population (P < 0.05 for all MR analyses). CRP was positively associated with tongue cancer, bronchitis, hydronephrosis, and acute pancreatitis and negatively associated with colorectal cancer, colon cancer, cerebral ischemia, electrolyte imbalance, Parkinson’s disease, epilepsy, anemia of chronic disease, encephalitis, psychophysical visual disturbances, and aseptic necrosis of bone in the UK Biobank. There were positive associations with impetigo, vascular dementia, bipolar disorders, hypercholesterolemia, vertigo, and neurological diseases, and negative correlations with degenerative macular diseases, metatarsalgia, interstitial lung disease, and idiopathic pulmonary fibrosis, and others. in the FinnGen population. The electrolyte imbalance and anemia of chronic disease in UK Biobank and hypercholesterolemia and neurological diseases in FinnGen pass the FDR corrections. Neurological diseases and bipolar disorders also presented positive genetic correlations with CRP. We found no overlapping causal associations between the populations. Previous causal evidence also failed to support these associations (except for bipolar disorders).ConclusionsGenetically determined CRP was robustly associated with several diseases in the UK Biobank and the FinnGen population, but could not be replicated, suggesting heterogeneous and non-repeatable effects of CRP across populations. This implies that interventions at CRP are unlikely to result in decreased risk for most human diseases in the general population but may benefit specific high-risk populations. The limited causal evidence and potential double-sided effects remind us to be cautious about CRP interventions.

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Sex differences in the impact of CYP2C19 polymorphisms and low-grade inflammation on coronary microvascular disorder

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00911.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. H1494-H1500 ◽

Cited By ~ 6

Author(s):

Tomonori Akasaka ◽

Seiji Hokimoto ◽

Daisuke Sueta ◽

Noriaki Tabata ◽

Kenji Sakamoto ◽

...

Keyword(s):

Sex Differences ◽

Risk Factor ◽

Confidence Interval ◽

Predictive Factors ◽

Odds Ratio ◽

Low Grade ◽

Cyp2c19 Genotype ◽

Hs Crp ◽

The Impact ◽

Low Grade Inflammation

Categorization as a cytochrome P-450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. It is correlated with an increase in the circulating levels of high-sense C-reactive protein (hs-CRP) in women only, although its role in coronary microcirculation is unclear. We examined sex differences in the impact of the CYP2C19 genotype and low-grade inflammation on coronary microvascular disorder (CMVD). We examined CYP2C19 genotypes in patients with CMVD ( n = 81) and in healthy subjects as control ( n = 81). CMVD was defined as the absence of coronary artery stenosis and epicardial spasms, the presence of inverted lactic acid levels between the intracoronary and coronary sinuses, or an adenosine triphosphate-induced coronary flow reserve ratio < 2.5. CYP2C19 PMs have two loss-of-function (LOF) alleles (*2, *3). Extensive metabolizers have no LOF alleles, and intermediate metabolizers have one LOF allele. The ratio of CYP2C19 PM and hs-CRP levels in CMVD was significantly higher than that of controls, especially in women (40.9 vs. 13.8%, P = 0.013; 0.11 ± 0.06 vs. 0.07 ± 0.04 mg/dl, P = 0.001). Moreover, in each CYP2C19 genotype, hs-CRP levels in CMVD in CYP2C19 PMs were significantly higher than those of the controls, especially in women (0.15 ± 0.06 vs. 0.07 ± 0.03, P = 0.004). Multivariate analysis for CMVD indicated that the female sex, current smoking, and hypertension were predictive factors, and that high levels of hs-CRP and CYP2C19 PM were predictive factors in women only (odds ratio 3.5, 95% confidence interval 1.26–9.93, P = 0.033; odds ratio 4.1, 95% confidence interval 1.15–14.1, P = 0.038). CYP2C19 PM genotype may be a new candidate risk factor for CMVD via inflammation exclusively in the female population.

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Shift work, low-grade inflammation, and chronic pain: a 7-year prospective study

International Archives of Occupational and Environmental Health ◽

10.1007/s00420-020-01626-2 ◽

2021 ◽

Author(s):

Jan Olav Christensen ◽

Kristian Bernhard Nilsen ◽

Laila Arnesdatter Hopstock ◽

Ólöf Anna Steingrímsdóttir ◽

Christopher Sivert Nielsen ◽

...

Keyword(s):

Chronic Pain ◽

Shift Work ◽

Chronic Widespread Pain ◽

Leg Pain ◽

Low Grade ◽

Low Back ◽

Serum Samples ◽

Mediation Analyses ◽

Reactive Protein ◽

Low Grade Inflammation

Abstract Objectives We investigated prospective associations of shift work with chronic pain and C‐reactive protein (CRP), an indicator of inflammation. Furthermore, we elucidated CRP as a possible mediator and/or moderator of effects of shift work on pain. Methods Data from a 7 years follow‐up study were analyzed (N = 2323). Shift work and chronic pain of “neck/shoulder”, “arm/hand”, “upper back”, “low back”, “hip/leg/feet”, and “other regions” were measured by questionnaires. “Chronic widespread pain”, “number of chronic pain sites”, and “any chronic pain” were computed. CRP was measured in serum samples. Logistic and Poisson regressions were conducted. Mediation was assessed by casual mediation analyses and moderation by the Relative Excess Risk due to Interaction (RERI). Results Shift work was not associated with any chronic pain variable and no mediation was detected. CRP was associated with low back pain, hip/leg pain, and “number of pain sites”, and also with the combination of shift work and CRP of 1–2.99 mg/L (compared to: no shiftwork and CRP < 1). Additionally, shiftwork and CRP 1–2.99 mg/L was associated with risk of “any chronic pain” (OR: 1.76, 95% CI: 1.12, 2.85), which was not associated with CRP alone. Moderation analyses suggested the risks for “any chronic pain” and “number of pain regions” increased when individuals with elevated CRP worked shifts—beyond what the separate effects of CRP and shift would suggest. Conclusions We found no evidence of shift work in general affecting CRP or chronic pain. However, shift work and elevated CRP combined may influence chronic pain.

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Low Nonfasting Triglycerides and Reduced All-Cause Mortality: A Mendelian Randomization Study

Clinical Chemistry ◽

10.1373/clinchem.2013.219881 ◽

2014 ◽

Vol 60 (5) ◽

pp. 737-746 ◽

Cited By ~ 84

Author(s):

Mette Thomsen ◽

Anette Varbo ◽

Anne Tybjærg-Hansen ◽

Børge G Nordestgaard

Keyword(s):

Odds Ratio ◽

Mendelian Randomization ◽

Hazard Ratio ◽

Plasma Triglycerides ◽

Hazard Ratios ◽

Remnant Lipoproteins ◽

Low Concentrations ◽

Heart Study ◽

All Cause Mortality ◽

Remnant Cholesterol

Abstract BACKGROUND Increased nonfasting plasma triglycerides marking increased amounts of cholesterol in remnant lipoproteins are important risk factors for cardiovascular disease, but whether lifelong reduced concentrations of triglycerides on a genetic basis ultimately lead to reduced all-cause mortality is unknown. We tested this hypothesis. METHODS Using individuals from the Copenhagen City Heart Study in a mendelian randomization design, we first tested whether low concentrations of nonfasting triglycerides were associated with reduced all-cause mortality in observational analyses (n = 13 957); second, whether genetic variants in the triglyceride-degrading enzyme lipoprotein lipase, resulting in reduced nonfasting triglycerides and remnant cholesterol, were associated with reduced all-cause mortality (n = 10 208). RESULTS During a median 24 and 17 years of 100% complete follow-up, 9991 and 4005 individuals died in observational and genetic analyses, respectively. In observational analyses compared to individuals with nonfasting plasma triglycerides of 266–442 mg/dL (3.00–4.99 mmol/L), multivariably adjusted hazard ratios for all-cause mortality were 0.89 (95% CI 0.78–1.02) for 177–265 mg/dL (2.00–2.99 mmol/L), 0.74 (0.65–0.84) for 89–176 mg/dL (1.00–1.99 mmol/L), and 0.59 (0.51–0.68) for individuals with nonfasting triglycerides <89 mg/dL (<1.00 mmol/L). The odds ratio for a genetically derived 89-mg/dL (1-mmol/L) lower concentration in nonfasting triglycerides was 0.50 (0.30–0.82), with a corresponding observational hazard ratio of 0.87 (0.85–0.89). Also, the odds ratio for a genetically derived 50% lower concentration in nonfasting triglycerides was 0.43 (0.23–0.80), with a corresponding observational hazard ratio of 0.73 (0.70–0.77). CONCLUSIONS Genetically reduced concentrations of nonfasting plasma triglycerides are associated with reduced all-cause mortality, likely through reduced amounts of cholesterol in remnant lipoproteins.

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Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels

Psychological Medicine ◽

10.1017/s0033291719001454 ◽

2019 ◽

Vol 49 (12) ◽

pp. 1958-1970 ◽

Cited By ~ 45

Author(s):

Emanuele Felice Osimo ◽

Luke James Baxter ◽

Glyn Lewis ◽

Peter B. Jones ◽

Golam M. Khandaker

Keyword(s):

Odds Ratio ◽

Antidepressant Treatment ◽

Meta Analysis ◽

Population Based ◽

Low Grade ◽

Healthy Controls ◽

Number Of Patients ◽

Pubmed Database ◽

Show Evidence ◽

Low Grade Inflammation

AbstractBackgroundPeripheral low-grade inflammation in depression is increasingly seen as a therapeutic target. We aimed to establish the prevalence of low-grade inflammation in depression, using different C-reactive protein (CRP) levels, through a systematic literature review and meta-analysis.MethodsWe searched the PubMed database from its inception to July 2018, and selected studies that assessed depression using a validated tool/scale, and allowed the calculation of the proportion of patients with low-grade inflammation (CRP >3 mg/L) or elevated CRP (>1 mg/L).ResultsAfter quality assessment, 37 studies comprising 13 541 depressed patients and 155 728 controls were included. Based on the meta-analysis of 30 studies, the prevalence of low-grade inflammation (CRP >3 mg/L) in depression was 27% (95% CI 21–34%); this prevalence was not associated with sample source (inpatient, outpatient or population-based), antidepressant treatment, participant age, BMI or ethnicity. Based on the meta-analysis of 17 studies of depression and matched healthy controls, the odds ratio for low-grade inflammation in depression was 1.46 (95% CI 1.22–1.75). The prevalence of elevated CRP (>1 mg/L) in depression was 58% (95% CI 47–69%), and the meta-analytic odds ratio for elevated CRP in depression compared with controls was 1.47 (95% CI 1.18–1.82).ConclusionsAbout a quarter of patients with depression show evidence of low-grade inflammation, and over half of patients show mildly elevated CRP levels. There are significant differences in the prevalence of low-grade inflammation between patients and matched healthy controls. These findings suggest that inflammation could be relevant to a large number of patients with depression.

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The health benefits of passive heating and aerobic exercise: To what extent do the mechanisms overlap?

Journal of Applied Physiology ◽

10.1152/japplphysiol.00608.2020 ◽

2020 ◽

Vol 129 (6) ◽

pp. 1304-1309

Author(s):

Tom Cullen ◽

Neil D. Clarke ◽

Mathew Hill ◽

Campbell Menzies ◽

Christopher J. A. Pugh ◽

...

Keyword(s):

Health Benefits ◽

Exercise Adherence ◽

Low Grade ◽

Vascular Health ◽

Passive Heating ◽

Physical Activity Guidelines ◽

Future Studies ◽

All Cause Mortality ◽

Exercise Induced ◽

Low Grade Inflammation

Exercise can induce numerous health benefits that can reduce the risk of chronic diseases and all-cause mortality, yet a significant percentage of the population do not meet minimal physical activity guidelines. Several recent studies have shown that passive heating can induce numerous health benefits, many of which are comparable with exercise, such as improvements to cardiorespiratory fitness, vascular health, glycemic control, and chronic low-grade inflammation. As such, passive heating is emerging as a promising therapy for populations who cannot perform sustained exercise or display poor exercise adherence. There appears to be some overlap between the cellular signaling responses that are regulated by temperature and the mechanisms that underpin beneficial adaptations to exercise, but detailed comparisons have not yet been made. Therefore, the purpose of this mini review is to assess the similarities and distinctions between adaptations to passive heating and exercise. Understanding the potential shared mechanisms of action between passive heating and exercise may help to direct future studies to implement passive heating more effectively and identify differences between passive heating and exercise-induced adaptations.

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