Causal effects of inflammation on long-term mortality: A mendelian randomization study.

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

Background: Cardiac troponins and biomarkers of inflammation are elevated in heart failure (HF) and predict cardiovascular risk. Whether these biomarkers associate with risk of ventricular arrhythmias (VA) is unclear. Purpose: To assess whether cardiac Troponin T (cTnT), growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations are associated with incident VA. Methods: In a prospective, observational study of patients treated with implantable cardioverter defibrillator (ICD), cTnT, GDF-15, IL-6, and CRP were measured at baseline and after 1.4±0.5y, and associated with ICD-detected incident VA, HF hospitalizations and mortality. Results: We included 489 patients, aged 66±12y and 83% were men. Median (quartile 1-3) concentrations of cTnT were 15 (9-25) ng/L at inclusion, and higher concentrations were associated with higher age, male sex, diabetes mellitus, coronary artery disease (CAD), and HF. During 3.1±0.7y follow-up, 137 (28%) patients had ≥1 VA. cTnT concentrations were associated with an increased VA risk (HR 1.63 [95% CI 1.31-2.01] per log-unit, p<0.001), also after adjustment for age, sex, BMI, CAD, HF, renal function, and LVEF (p<0.001). GDF-15, IL-6, and CRP concentrations were not associated with incident VA, but all (including cTnT) were associated with HF hospitalization and mortality. Changes in cTnT, GDF-15, IL-6, and CRP from baseline to 1.4y were not associated with subsequent VA. Conclusions: Higher concentrations of cTnT, GDF-15, IL-6, and CRP associate with HF hospitalization and death, but only cTnT predicts incident VA. These findings suggest that myocardial injury rather than inflammation may play a pathophysiological role in VA and sudden cardiac death.

Depression and interleukin-6 signaling: A Mendelian Randomization study

Background: Subjects with osteoarthritis (OA) are at increased risk for cardiovascular (CV) and all-cause mortality. Whether biomarkers improve outcome prediction in these patients remains to be elucidated. We investigated the association between growth differentiation factor 15 (GDF-15), a novel stress-responsive cytokine, and long-term all-cause mortality among OA patients. Methods: Within the Ulm Osteoarthritis Study, GDF-15 has been measured in the serum of 636 subjects, who underwent hip or knee arthroplasty between 1995 and 1996 (median age 65 years). Results: During a median follow-up of 19.7 years, a total of 402 deaths occurred. GDF-15 was inversely associated with walking distance. Compared to the bottom quartile (Q), subjects within the top quartile of GDF-15 demonstrated a 2.69-fold increased risk of dying (hazard ratio (HR) (95% confidence interval (CI)) 2.69 (1.82–3.96) adjusted for age, sex, BMI, smoking status, localization of OA, diabetes, maximum walking distance, total cholesterol, and cystatin C. Further adjustment for NT-proBNP, troponin I, and hs-C-reactive protein did not change the results appreciably (HR (95%CI) 1.56 (1.07–2.28); 1.75 (1.21–2.55); 2.32 (1.55–3.47) for Q2, Q3, and Q4 respectively, p for trend < 0.001). Conclusions: In subjects with OA, GDF-15 represents a potent predictor of decreased survival over >20 years, independently of conventional CV risk factors, renal, cardiac, and inflammatory biomarkers as well as walking disability, previously associated with increased mortality and lower extremity OA.

Dietary inflammatory potential has been proven to be correlated with the incidence of diabetes and cardiovascular diseases. However, the evidence regarding the impact of dietary inflammatory patterns on long-term mortality is scarce. This cohort study aims to investigate the dietary inflammatory pattern of the general US individuals by baseline glycemic status and to estimate its association with long-term mortality. A total of 20,762 general American adults with different glycemic statuses from the National Health and Nutrition Examination Survey were included. We extracted 24-h dietary information, and the dietary inflammatory index (DII) was calculated. The outcomes were defined as 5-year all-cause and cardiovascular mortality. Compared with the normoglycemia group, individuals with prediabetes and type 2 diabetes had higher DII scores (overall weighted p < 0.001). Compared with low DII scores, participants with high DII scores were at a higher risk of long-term all-cause mortality (HR: 1.597, 95% CI: 1.370, 1.861; p < 0.001) and cardiovascular mortality (HR: 2.036, 95% CI: 1.458, 2.844; p < 0.001). The results were stable after adjusting for potential confounders. Moreover, the prognostic value of DII for long-term all-cause mortality existed only in diabetic individuals but not in the normoglycemia or prediabetes group (p for interaction = 0.006). In conclusion, compared to the normoglycemia or prediabetes groups, participants with diabetes had a higher DII score, which indicates a greater pro-inflammatory potential. Diabetic individuals with higher DII scores were at a higher risk of long-term all-cause and cardiovascular mortality.

To examine whether delirium in individuals with hip fracture is associated with high C-reactive protein (CRP), interleukin-6 (IL-6), and soluble IL-6 receptor (sIL-6R) levels in the cerebrospinal fluid (CSF). Prospective cohort study. Two university hospitals in Oslo, Norway, and Edinburgh, United Kingdom. Individuals admitted with acute hip fracture (N = 151). Participants were assessed for delirium pre- and postoperatively using the Confusion Assessment Method. Prefracture cognitive impairment was detected using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Serum was collected preoperatively and CSF just before the onset of spinal anesthesia. Cytokine levels in serum and CSF samples were determined using an enzyme-linked immunosorbent assay. Student t-tests or Mann-Whitney U-tests were used for between-group comparisons. Spearman rho was used for correlations. Sixty participants had prior cognitive impairment (IQCODE score ≥3.44). Delirium was diagnosed in 46 participants (77%) with prior cognitive impairment and 25 (29%) without. In participants without prior cognitive impairment, CSF CRP levels were higher in participants with delirium (median 0.05 μg/mL, interquartile range (IQR) 0.02-0.12 μg/mL) than in those without delirium (median 0.01 μg/mL, IQR 0.00-0.06 μg/mL) (P = .01); there were no differences in participants with prior cognitive impairment. In secondary analyses, in participants with prior cognitive impairment, the concentration of CSF sIL-6R was higher in those participants who developed delirium than in the other subgroups, but this difference was not statistically significant. Serum levels of CRP, IL-6, and sIL-6R were not different according to delirium in participants with or without prefracture cognitive impairment. High CSF levels of CRP and sIL-6R may be associated with delirium. Different pathophysiological mechanisms may operate in different subgroups, notably in relation to the presence of prior cognitive impairment.

Lung cancer (LC) screening can be optimized using individuals' estimated risks of having a detectable lung tumor, as well as of mortality risk by competing causes, to guide decisions on screening eligibility, ideal screening intervals and stopping ages. Besides age, sex and smoking history, blood-based biomarkers may be used to improve the assessment of LC risk and risk of mortality by competing causes. In the German randomized Lung Screening Intervention Trial (LUSI), we measured growth/differentiation factor-15 (GDF-15), interleukin-6 (IL-6), C-reactive protein (CRP) and N-terminal pro-brain natriuretic protein (NT-proBNP), in blood serum samples collected at start of the trial. Participants in the computed tomography (CT)-screening arm also had a pulmonary function test. Regression models were used to examine these markers as predictors for impaired lung function, LC risk and mortality due to LC or other causes, independently of age, sex and smoking history. Our models showed increases in LC risk among participants with elevated serum levels of GDF-15 [odds ratio (OR)Q4-Q1 =2.47, 95% confidence interval (CI): 1.49-4.26], IL-6 [ORQ4-Q1 =2.36 (1.43-4.00)] and CRP [ORQ4-Q1 =1.81 (1.08-2.75)]. Likewise, proportional hazards models showed increased risks for LC-related mortality, hazard ratio (HR)Q4-Q1 of 4.63 (95% CI: 2.13-10.07) for GDF-15, 3.56 (1.72-7.37) for IL-6 and 2.34 (1.24-4.39) for CRP. All four markers were associated with increased risk of mortality by causes other than LC, with strongest associations for GDF-15 [HRQ4-Q1 =3.04 (2.09-4.43)] and IL-6 [HRQ4-Q1 =2.98 (2.08-4.28)]. Significant associations were also observed between IL-6, CRP, GDF-15 and impaired pulmonary function [chronic obstructive pulmonary disease (COPD), preserved ratio impaired spirometry (PRISm)]. Multi-marker models identified GDF-15 and IL-6 as joint risk predictors for risk of LC diagnosis, without further discrimination by CRP or NT-proBNP. A model based on age, sex, smoking-related variables, GFD-15 and IL-6 provided moderately strong discrimination for prediction of LC diagnoses within 9 years after blood sampling [area under the curve (AUC) =74.3% (57.3-90.2%)], compared to 67.0% (49.3-84.8%) for a model without biomarkers. For mortality by competing causes, a model including biomarkers resulted in an AUC of 76.2% (66.6-85.3%)], compared to 70.0% (60.9-77.9%) a model including age, sex and smoking variables. Serum GDF-15 and IL-6 may be useful indicators for estimating risks for LC and competing mortality among long-term smokers participating in LC screening, to optimize LC screening strategies.

Current evidence linking sedentary behavior (SB), physical activity (PA), and inflammation raises questions about their causal relationships, prompting concerns about potential residual confounding or reverse causation. A bidirectional Mendelian randomization (MR) analysis was conducted. SB data (n = 408,815) from "computer use," "television watching," and "driving" were included. The PA data encompassed nine types of PA (n = 460,376) over the last four weeks and included data on the frequency of vigorous PA (n = 440,512) and moderate PA (n = 440,266) for over 10 min. Additionally, three genome-wide association study datasets (n = 64,949) on light, moderate, and vigorous exercise were included to minimize potential bias from changes in exercise intensity. Inflammation data included levels of C-reactive protein (CRP) (n = 575,531), glycoprotein acetyl (GlycA) (n = 115,082), interleukin (IL)-8, IL-6, IL-6 receptor (IL-6R), and soluble IL-6R (sIL-6R) (n = 35,278). All datasets represented participants of European ancestry. Television watching as an SB showed significant positive causal effects on GlycA and CRP (inverse variance weighted (IVW), odds ratios (OR): 1.34, 95% confidence intervals (CI): 1.25-1.44, p = 3.570 × 10-17; IVW, OR: 1.21, 95% CI: 1.16-1.26, p = 1.500 × 10-19, respectively), with more robust evidence for GlycA. In the direction from inflammation to PA, a negative causal relationship between CRP and"number of days/week of moderate PA 10+ minutes"was observed (IVW, OR: 0.92, 95% CI: 0.89-0.96, p = 3.260 × 10-5). Sensitivity analyses were used to verify the robustness and reliability of the results. However, other initially observed associations ceased to be significant after controlling for obesity-related confounders. Our MR analysis suggested a potential causal relationship between television watching and chronic low-grade inflammation, with more substantial evidence for GlycA. Additionally, different types of SB may have varying effects on inflammation. Obesity-related traits could partly or entirely influence the relationship between SB, PA, and inflammatory markers. Furthermore, Our findings indicate that SB is an independent risk factor for inflammation, separate from PA, and highlight the different mechanisms by which SB and PA affect disease.

Objective To determine the prognostic significance of non-thyroidal illness syndrome(NTIS)and FT3 on long-term all-cause and cardiovascular mortality in patients with coronary artery disease(CAD). Methods A total of 1 354 patients underwent coronary angiograhy and participated in the study. After screening, 984 patients with CAD were enrolled finally and divided into NTIS group and euthyroid group. The admitted patients were also classified into Tertile 1-3 groups based on FT3 value. The relationship of long-term all-cause and cardiovascular mortality with FT3 was investigated by multivariate Cox regression analysis. Results 129 out of 984 patients had NTIS. As FT3 value decreased, both long-term all-cause mortality(Tertile 1 group 9.6%, Tertile 2 group 11.5%, Tertile 3 group 20.9%, P<0.01)and cardiovascular mortality(Tertile 1 group 4.5%, Tertile 2 group 7.2%, Tertile 3 group 11.0%, P<0.01)gradually increased. After adjusting for all factors, FT3(HR=0.614, 95%CI 0.439-0.859)was independently associated with long-term all-cause mortality. FT3(HR=0.605, 95%CI 0.370-0.986)was also a risk factor for cardiovascular mortality. Conclusion NTIS exists in patients with CAD without myocardial infarction. FT3 reduction is an independent risk factor for long-term all-cause and cardiovascular mortality in patients with CAD. (Chin J Endocrinol Metab, 2015, 31: 47-51) Key words: Non-thyroidal illness syndrome; Coronary artery disease; Long-term mortality

Background and objectivesElevated C-reactive protein (CRP) is a well-established marker of low-grade systemic inflammation often accompanying cardiometabolic diseases like type 2 diabetes. We sought to determine if plasma CRP concentrations can be used as a predictive marker of risk for ischemic stroke and all-cause death in the general population, and to investigate whether elevated plasma CRP has a causal effect on ischemic stroke and all-cause death.MethodsObservational and one-sample Mendelian randomization analyses were performed in 113,491 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study. Two-sample Mendelian randomization analyses were performed in up to 575,531 individuals with publicly available data from the CHARGE CIWG, UKBB, FinnGen, and MEGASTROKE.ResultsObservationally in the Copenhagen studies, higher CRP concentrations associated with stepwise higher risk of ischemic stroke and all-cause death with the highest hazard ratios of 1.51(95% confidence interval: 1.34, 1.71) and 1.69(1.60, 1.79), respectively. The cumulative incidence of ischemic stroke at age 72 was 57% higher and the cumulative incidence of all-cause death at age 80 was 62% higher in individuals with a plasma CRP ≥ 2 mg/L compared to individuals with a plasma CRP < 2 mg/L. One- and two-sample Mendelian randomization analyses did not support a causal effect of CRP on risk of ischemic stroke, nor of CRP on risk of all-cause death, with odds ratios in studies combined of 1.01(0.98, 1.05) and 1.01(0.98, 1.05), respectively.ConclusionIn this observational and one- and two-sample Mendelian randomization study, we found that elevated CRP concentrations above the population median of 1.4 mg/L predicted risk of ischemic stroke and all-cause death. There was no causal genetic effect of C-reactive protein on risk of stroke or all-cause death.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12933-025-03028-5.

IDF21-0383 Circulating GDF15 Predicted Mortality in Aging Chinese People with Type 2 Diabetes: Findings from Da Qing Diabetes Study

The metabolic syndrome, a combination of interrelated metabolic risk factors, is associated with insulin resistance and promotes the development of cardiovascular diseases and type 2 diabetes mellitus. There is a close link between inflammation and metabolic disease, but the responsible mechanisms remain elusive. The aim of this study was to identify differentially expressed genes in insulin-resistant skeletal muscle tissue of women with the metabolic syndrome compared with healthy control women. Women with the metabolic syndrome (n = 19) and healthy control women (n = 20) were extensively phenotyped, insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp, and a skeletal muscle biopsy was obtained. Gene expression levels were compared between the two groups by microarrays. The upregulated genes in skeletal muscle of the women with the metabolic syndrome were primarily enriched for inflammatory response-associated genes. The three most significantly upregulated of this group, interleukin 6 receptor (IL6R), histone deacetylase 9 (HDAC9) and CD97 molecule (CD97), were significantly correlated with insulin resistance. Taken together, these findings suggest an important role for a number of inflammatory-related genes in the development of skeletal muscle insulin resistance.

Prospective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring possible causality. We aimed to assess the causal associations of these cardiac blood biomarkers with dementia and cognition using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e−7) for troponin T and I, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth-differentiation factor 15 (GDF15) were obtained from previously-performed genome-wide association studies of predominantly European ancestry. Summary statistics for gene-outcome associations in European-ancestry participants, for the two-sample MR analyses, were obtained for general cognitive performance (n = 257,842) and dementia (n = 111,326 clinically diagnosed and “proxy” AD cases, and 677,663 controls). Two-sample MR analyses were performed using inverse variance-weighted (IWV) analyses. Sensitivity analyses to evaluate horizontal pleiotropy included weighted median estimator, MR-Egger, and MR using cis-SNPs only. Using IVW, we did not find evidence for possible causal associations between genetically influenced cardiac biomarkers with cognition and dementia. For example, per standard deviation (SD) higher cardiac blood biomarker, the odds ratio for risk of dementia was 1.06 (95%CI 0.90; 1.21) for troponin T, 0.98 (95%CI 0.72; 1.23) for troponin I, 0.97 (95%CI 0.90; 1.06) for NT-proBNP and 1.07 (95%CI 0.93; 1.21) for GDF15. Sensitivity analyses showed higher GDF15 was significantly associated with higher dementia risk and worse cognitive function. We did not find strong evidence that cardiac biomarkers causally influence dementia risk. Future research should aim at elucidating the biological pathways through which cardiac blood biomarkers associate with dementia.

Type II collagen is composed of alpha1(II) chains encoded by the COL2A1 gene. Alteration of this cartilage marker is a common feature of osteoarthritis. Interleukin-6 (IL-6) is a pro-inflammatory cytokine that needs a soluble form of receptor called sIL-6R to exert its effects in some cellular models. In that case, sIL-6R exerts agonistic action. This mechanism can make up for the partial or total absence of membrane-anchored IL-6 receptors in some cell types, such as chondrocytes. Our study shows that IL-6, sIL-6R, or both inhibit type II collagen production by rabbit articular chondrocytes through a transcriptional control. The cytokine and/or sIL-6R repress COL2A1 transcription by a -63/-35 sequence that binds Sp1.Sp3. Indeed, IL-6 and/or sIL-6R inhibit Sp1 and Sp3 expression and their binding activity to the 63-bp promoter. In chromatin immunoprecipitation experiments, IL-6.sIL-6R induced an increase in Sp3 recruitment to the detriment of Sp1. Knockdown of Sp1.Sp3 by small interference RNA and decoy strategies were found to prevent the IL-6- and/or sIL-6R-induced inhibition of COL2A1 transcription, indicating that each of these Sp proteins is required for down-regulation of the target gene and that a heterotypic Sp1.Sp3 complex is involved. Additionally, Sp1 was shown to interact with Sp3 and HDAC1. Indeed, overexpression of a full-length Sp3 cDNA blocked the Sp1 up-regulation of the 63-bp COL2A1 promoter activity, and by itself, inhibits COL2A1 transcription. We can conclude that IL-6, sIL-6R, or both in combination decrease both the Sp1.Sp3 ratio and DNA-binding activities, thus inhibiting COL2A1 transcription.

Telomere shortening is an important sign and driving factor of aging, but its association mechanisms and causal effects with other aging-related biochemical hallmarks are largely unknown. This study first performed comprehensive genetic analyses (eg, shared genetic analysis, pleiotropic analysis, and gene enrichment analysis) to detect the underlying molecular mechanisms for the associations between telomere length (TL) and aging-related biochemical hallmarks. Then, further bidirectional Mendelian randomization (MR) analyses investigated the causal effects between TL and other biochemical hallmarks. The genetic correlations were negative between TL and growth differentiation factor-15 (GDF15) (p = .024), C-reactive protein (p = .007), hemoglobin A1c (p = .007), and red blood cell (RBC) (p = .022), but positive between TL and insulin-like growth factor 1 (IGF-1) (p = .002) and white blood cell counts (p = .007). The increased TL has causal effects on the low levels of GDF15 (p = 3.73E-06), sex hormone binding globulin (p = 6.30E-06), testosterone (p = 5.56E-07), fasting insulin (p = 2.67E-05), and RBC (p = 1.54E-05), but the higher levels of IGF-1 (p = 3.24E-07). In conclusion, the observed phenotypic correlations between TL and aging-related biochemical hallmarks may arise from a combination of shared genetic components and causal effects. Telomere length is regarded as a driving hallmark for aging-related biochemical hallmarks.