Browsing by Subject "Inflammation"

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  • Drug-Induced Liver Injury Network; Int DILI Consortium iDILIC; Cirulli, Elizabeth T.; Nicoletti, Paola; Laitinen, Tarja (2019)
    BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
  • Lindfors, S; Polianskyte-Prause, Z; Bouslama, R; Lehtonen, E; Mannerla, M; Nisen, H; Tienari, J; Salmenkari, H; Forsgard, R; Mirtti, T; Lehto, M; Groop, PH; Lehtonen, S (2021)
    Aims/hypothesis Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist. Methods Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration. Results In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-kappa B p65 subunit (NF-kappa B-p65) (70%, p < 0.001), TNF alpha (48%, p < 0.01), IL-1 beta (51%, p < 0.001) and TGF beta (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-kappa B-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNF alpha (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1 beta, IL-18, IL-6 and IL-10. Conclusions/interpretation AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-kappa B-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNF alpha. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.
  • Kochumon, Shihab; Arefanian, Hossein; Sindhu, Sardar; Shenouda, Steve; Thomas, Reeby; Al-Mulla, Fahd; Tuomilehto, Jaakko; Ahmad, Rasheed (2021)
    Steroid receptor RNA activator 1 (SRA1) is involved in pathophysiological responses of adipose tissue (AT) in obesity. In vitro and animal studies have elucidated its role in meta-inflammation. Since SRA1 AT expression in obesity/type 2 diabetes (T2D) and the relationship with immune-metabolic signatures remains unclear, we assessed AT SRA1 expression and its association with immune–metabolic markers in individuals with obesity/T2D. For this, 55 non-diabetic and 53 T2D individuals classified as normal weight (NW; lean), overweight, and obese were recruited and fasting blood and subcutaneous fat biopsy samples were collected. Plasma metabolic markers were assessed using commercial kits and AT expression of SRA1 and selected immune markers using RT-qPCR. SRA1 expression was significantly higher in non-diabetic obese compared with NW individuals. SRA1 expression associated with BMI, PBF, serum insulin, and HOMA-IR in the total study population and people without diabetes. SRA1 associated with waist circumference in people without diabetes and NW participants, whereas it associated inversely with HbA1c in overweight participants. In most study subgroups AT SRA1 expression associated directly with CXCL9, CXCL10, CXCL11, TNF-α, TGF-β, IL2RA, and IL18, but inversely with CCL19 and CCR2. TGF-β/IL18 independently predicted the SRA1 expression in people without diabetes and in the total study population, while TNF-α/IL-2RA predicted SRA1 only in people with diabetes. TNF-α also predicted SRA1 in both NW and obese people regardless of the diabetes status. In conclusion, AT SRA1 expression is elevated in people with obesity which associates with typical immunometabolic markers of obesity/T2D, implying that SRA1 may have potential as a biomarker of metabolic derangements.
  • Eriksson, Mia D.; Eriksson, Johan G.; Kautiainen, Hannu; Salonen, Minna K.; Mikkola, Tuija M.; Kajantie, Eero; Wasenius, Niko; von Bonsdorff, Mikaela; Laine, Merja K. (2021)
    Background: Millions of people live with depression and its burden of disease. Depression has an increased comorbidity and mortality that has remained unexplained. Studies have reported connections between advanced glycation end products (AGEs) and various disease processes, including mental health. The present study evaluated associations between AGEs, depressive symptoms, and types of depressive symptoms. Methods: From the Helsinki Birth Cohort Study, 815 participants with a mean age of 76 years were recruited for this cross-sectional study. Characteristics regarding self-reported lifestyle and medical history, as well as blood tests were obtained along with responses regarding depressive symptoms according to the Beck Depression Inventory (BDI) and Mental Health Inventory-5. Each participant had their AGE level measured non-invasively with skin autofluorescence (SAF). Statistical analyses looked at relationships between types of depressive symptoms and AGE levels by sex. Results: Of women, 27% scored >= 10 on the BDI and 18% of men, respectively. Men had higher crude AGE levels (mean [standard deviation], arbitrary units) (2.49 [0.51]) compared to women (2.33 [0.46]) (p < 0.001). The highest crude AGE levels were found in those with melancholic depressive symptoms (2.61 [0.57]), followed by those with non-melancholic depressive symptoms (2.45 [0.45]) and those with no depressive symptoms (2.38 [0.49]) (p = 0.013). These findings remained significant in the fully adjusted model. Conclusions: The current study shows an association between depressive symptoms and higher AGE levels. The association is likely part of a multi-factorial effect, and hence no directionality, causality, or effect can be inferred solely based on the results of this study.
  • Tanila, Heikki; Hiltunen, Mikko; Myllykangas, Liisa (2018)
  • Miettinen, Jenni; Tainio, Juuso; Jahnukainen, Timo; Pakarinen, Mikko; Lauronen, Jouni; Jalanko, Hannu (2017)
    Anemia and low-grade inflammation are reported to be associated with impaired long-term graft outcome in renal transplant (RTx) recipients. In this study, hemoglobin (Hb) and inflammation marker levels were correlated with measured glomerular filtration rate (GFR) in 128 pediatric RTx recipients over a median follow-up period of 10 years. Serum levels of erythropoietin (EPO), hepcidin-25, high-sensitivity C-reactive protein (CRP) (hsCRP) and interleukin-6 (IL-6) were analyzed by enzyme-linked immunosorbent assays, and GFR was analyzed by Cr-51-EDTA clearance. The median levels of Hb (115 g/L), hsCRP (0.4 mg/L) and IL-6 (1.4 pg/mL) and the median erythrocyte sedimentation rate (ESR; 19 mm/h) remained stable after the first post-operative year. However, approximately half of the patients had a normocytic, normochromic anemia, and one-third had elevated levels of hsCRP (> 1 mg/L) and ESR (> 25 mm/h), indicating continuous low-grade inflammation. Low Hb levels preceded increased fibrosis in protocol biopsies taken at 1.5 and 3 years after transplantation and preceded decreased GFR by several years. Hb levels showed an inverse correlation with EPO levels (r = -0.206, p = 0.038) and ESR (r = -0.369, p <0.001), but not with hepcidin-25, hsCRP or IL-6 levels. The levels of the major inflammatory markers IL-6 and hsCRP did not show a significant correlation with GFR at either the early maintenance phase or later. In the multivariable analysis, low Hb levels performed better than any other marker with respect to predicting concomitant and subsequent GFR. Anemia, but not elevated inflammatory indices, was associated with poor concomitant and subsequent graft function during a 10-year follow-up in pediatric RTx patients.
  • Haapamäki, Johanna (2016)
    Anemia on yleistä tulehduksellisissa suolistosairauksissa. Se on tavallisimmin raudanpuuteanemia, kroonisen taudin anemia tai näiden yhdistelmä. Ohutsuolen loppuosan poisto aiheuttaa B12-vitamiinin puutteen riskiAnemia huonontaa potilaiden elämänlaatua ja työ- ja toimintakykyä. Tulehduksellista suolistosairautta sairastavat eivät useinkaan siedä suun kautta annettavaa rautahoitoa, ja heille parenteraalinen rautahoito on hyvä vaihtoehto.
  • Mäkelä, Kati; Mäyränpää, Mikko I.; Sihvo, Hanna-Kaisa; Bergman, Paula; Sutinen, Eva; Ollila, Hely; Kaarteenaho, Riitta; Myllärniemi, Marjukka (2021)
    A large number of fibroblast foci (FF) predict mortality in idiopathic pulmonary fibrosis (IPF). Other prognostic histological markers have not been identified. Artificial intelligence (AI) offers a possibility to quantitate possible prognostic histological features in IPF. We aimed to test the use of AI in IPF lung tissue samples by quantitating FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with a deep convolutional neural network (CNN). Lung tissue samples of 71 patients with IPF from the FinnishIPF registry were analyzed by an AI model developed in the Aiforia® platform. The model was trained to detect tissue, air spaces, FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with 20 samples. For survival analysis, cut-point values for high and low values of histological parameters were determined with maximally selected rank statistics. Survival was analyzed using the Kaplan-Meier method. A large area of FF predicted poor prognosis in IPF (p = 0.01). High numbers of interstitial mononuclear inflammatory cells and intra-alveolar macrophages were associated with prolonged survival (p = 0.01 and p = 0.01, respectively). Of lung function values, low diffusing capacity for carbon monoxide was connected to a high density of FF (p = 0.03) and a high forced vital capacity of predicted was associated with a high intra-alveolar macrophage density (p = 0.03). The deep CNN detected histological features that are difficult to quantitate manually. Interstitial mononuclear inflammation and intra-alveolar macrophages were novel prognostic histological biomarkers in IPF. Evaluating histological features with AI provides novel information on the prognostic estimation of IPF.
  • Eskelinen, Eeva-Liisa (2019)
    Autophagy is a conserved catabolic process that delivers cytoplasmic components and organelles to lysosomes for degradation and recycling. This pathway serves to degrade nonfunctional organelles and aggregate-prone proteins, as well as to produce substrates for energy production and biosynthesis. Autophagy is especially important for the maintenance of stem cells, and for the survival and homeostasis of post-mitotic cells like neurons. Functional autophagy promotes longevity in several model organisms. Autophagy regulates immunity and inflammation at several levels and has both anti- and pro-tumorigenic roles in cancer. This review provides a concise overview of autophagy and its importance in cellular and organismal homeostasis, with emphasis on aging, stem cells, neuronal cells, immunity, inflammation, and cancer.
  • Simonsen, Johan Rasmus; Järvinen, Asko; Hietala, Kustaa; Harjutsalo, Valma; Forsblom, Carol; Groop, Per-Henrik; Lehto, Markku (2021)
    Background/Aims Diabetic retinopathy (DR) is associated and shares many risk factors with other diabetic complications, including inflammation. Bacterial infections, potent inducers of inflammation have been associated with the development of diabetic complications apart from DR. Our aim was to investigate the association between bacterial infections and DR. Methods Adult individuals with type 1 diabetes (n=1043) were recruited from the Finnish Diabetic Nephropathy Study (FinnDiane), a prospective follow-up study. DR was defined as incident severe diabetic retinopathy (SDR), identified as first laser treatment. Data on DR were obtained through fundus photographs and medical records, data on bacterial infections from comprehensive national registries (1 January 1995 to 31 December 2015). Risk factors for DR and serum bacterial lipopolysaccharide (LPS) activity were determined at baseline. Results Individuals with incident SDR (n=413) had a higher mean number of antibiotic purchases/follow-up year compared with individuals without incident SDR (n=630) (0.92 [95% CI 0.82 to 1.02] vs 0.67 [0.62-0.73], p=0.02), as well as higher levels of LPS activity (0.61 [0.58-0.65] vs 0.56 [0.54-0.59] EU/mL, p=0.03). Individuals with on average >= 1 purchase per follow-up year (n=269) had 1.5 times higher cumulative incidence of SDR, compared with individuals with
  • Karaman, Sinem; Hollmen, Maija; Robciuc, Marius R.; Alitalo, Annamari; Nurmi, Harri; Morf, Bettina; Buschle, Dorina; Alkan, H. Furkan; Ochsenbein, Alexandra M.; Alitalo, Kari; Wolfrum, Christian; Detmar, Michael (2015)
    Objective: Elevated serum levels of the lymphangiogenic factors VEGF-C and -D have been observed in obese individuals but their relevance for the metabolic syndrome has remained unknown. Methods: K14-VEGFR-3-Ig (sR3) mice that constitutively express soluble-VEGFR-3eIg in the skin, scavenging VEGF-C and -D, and wildtype (WT) mice were fed either chow or high-fat diet for 20 weeks. To assess the effect of VEGFR-3 blockage on adipose tissue growth and insulin sensitivity, we evaluated weight gain, adipocyte size and hepatic lipid accumulation. These results were complemented with insulin tolerance tests, FACS analysis of adipose tissue macrophages, in vitro 3T3-L1 differentiation assays and in vivo blocking antibody treatment experiments. Results: We show here that sR3 mice are protected from obesity-induced insulin resistance and hepatic lipid accumulation. This protection is associated with enhanced subcutaneous adipose tissue hyperplasia and an increased number of alternatively-activated (M2) macrophages in adipose tissue. We also show that VEGF-C and -D are chemotactic for murine macrophages and that this effect is mediated by VEGFR-3, which is upregulated on M1 polarized macrophages. Systemic antibody blockage of VEGFR-3 in db/db mice reduces adipose tissue macrophage infiltration and hepatic lipid accumulation, and improves insulin sensitivity. Conclusions: These results reveal an unanticipated role of the lymphangiogenic factors VEGF-C and -D in the mediation of metabolic syndrome-associated adipose tissue inflammation. Blockage of these lymphangiogenic factors might constitute a new therapeutic strategy for the prevention of obesity-associated insulin resistance. (C) 2014 The Authors. Published by Elsevier GmbH.
  • Korhonen, Kati V. M.; Savolainen-Peltonen, Hanna; Mikkola, Tomi S.; Tiitinen, Aila E.; Unkila-Kallio, Leila S. (2016)
    Objectives: Many in vitro fertilization (IVF) complications are inflammatory by nature, some of which are even life-threatening. We evaluated the response of C-reactive protein (CRP) in IVF complications, especially in early and late ovarian hyperstimulation syndrome (OHSS), to support clinical decision making in gynecological emergency policlinics. Study design: In a prospective two-year study at Helsinki University Hospital, Finland, we recruited patients with IVF complications including moderate or severe OHSS (n = 47 patients: 36 early and 14 late OHSS cases), or other IVF complications (n = 13). As controls, we recruited women in an uncomplicated IVF cycle (n = 27). Serial blood samples (CRP, blood count, platelets, albumin, estradiol, creatinine, and electrolytes) were collected from patients upon admission to the emergency polyclinic and during and after treatment on the ward, and from the controls prior, during, and after the IVF protocol. All samples were categorized according to oocyte pick-up (OPU). The statistics included comparisons between and within the study groups, and receiver-operating characteristic (ROC) curve analysis for diagnostic accuracy of CRP for early OHSS at emergency polyclinics. Results: On admission, CRP did not differentiate OHSS from other IVF complications, but CRP was higher in early (median 21; IQR 8-33 mg/L) than in late (6; 3-9 mg/L, p = 0.001) OHSS. In ROC analysis for CRP (12 mg/L), the area under the curve (AUC) was 0.74 (p = 0.001) with sensitivity of 69% and specificity of 71% for early OHSS. CRP was significantly higher (28; 10-46 mg/L) in patients with early OHSS two days after oocyte pick-up (OPU) than in the controls (5; Conclusions: Early OHSS associates with a distinct rise in CRP level beyond that induced by uncomplicated oocyte pick-up, whereas the CRP levels in late OHSS are comparable to those in the control cycles. CRP identifies, but cannot distinguish IVF complications. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Simonen, Piia; Lehtonen, Jukka; Gylling, Helena; Kupari, Markku (2016)
    Background and aims: Patients with cardiac sarcoidosis (CS) suffer from myocardial inflammation, but atherosclerosis is not infrequent in these patients. However, the classical atherosclerotic risk factors, such as perturbed serum lipids and whole-body cholesterol metabolism, remain unravelled in CS. Methods: We assessed serum non-cholesterol sterols, biomarkers of whole-body cholesterol synthesis and cholesterol absorption efficiency, with gas-liquid chromatography in 39 patients with histologically verified CS and in an age-adjusted random population sample (n = 124). Results: CS was inactive or responding to treatment in all patients. Concentrations of serum, LDL, and HDL cholesterol and serum triglycerides were similar in CS patients and in control subjects. Cholesterol absorption markers were higher in CS patients than in controls (eg serum campesterol to cholesterol ratio in CS 246 +/- 18 vs in controls 190 +/- 8 10(2) x mu mol/mmol of cholesterol, p = 0.001). Cholesterol synthesis markers were lower in CS patients than in controls (eg serum lathosterol to cholesterol ratio in CS 102 +/- 8 vs in controls 195 +/- 5 10(2) x mu mol/mmol of cholesterol, p = 0.000). In CS patients, cholesterol absorption markers significantly correlated with plasma prohormone brain natriuretic peptide (proBNP), a marker of hemodynamic load. Conclusion: High cholesterol absorption efficiency, which is suggested to be atherogenic, characterized the metabolic profile of cholesterol in CS patients. The association between cholesterol absorption efficiency and plasma proBNP concentration, which suggests a link between inflammation, cholesterol homeostasis, and hemodynamic load, warrants further studies in order to confirm this finding and to reveal the underlying mechanisms. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • PRACTICAL Consortium; Bouras, Emmanouil; Karhunen, Ville; Gill, Dipender; Ahola-Olli, Ari; Mannikko, Minna; Auvinen, Juha; Herzig, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka; Lehtimäki, Terho; Salomaa, Veikko; Raitakari, Olli; Salmi, Marko; Jalkanen, Sirpa; Jarvelin, Marjo-Riitta; Tsilidis, Konstantinos K. (2022)
    Background Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.
  • Yeung, Edwina H; Guan, Weihua; Zeng, Xuehuo; Salas, Lucas A; Mumford, Sunni L; de Prado Bert, Paula; van Meel, Evelien R; Malmberg, Anni; Sunyer, Jordi; Duijts, Liesbeth; Felix, Janine F; Czamara, Darina; Hämäläinen, Esa; Binder, Elisabeth B; Räikkönen, Katri; Lahti, Jari; London, Stephanie J; Silver, Robert M; Schisterman, Enrique F (BioMed Central, 2020)
    Abstract Background Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed. Results Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (< 18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p < 0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes. Conclusions Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways. Trial registration Clinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363
  • Yeung, Edwina H.; Guan, Weihua; Zeng, Xuehuo; Salas, Lucas A.; Mumford, Sunni L.; de Prado Bert, Paula; van Meel, Evelien R.; Malmberg, Anni; Sunyer, Jordi; Duijts, Liesbeth; Felix, Janine F.; Czamara, Darina; Hämäläinen, Esa; Binder, Elisabeth B.; Räikkönen, Katri; Lahti, Jari; London, Stephanie J.; Silver, Robert M.; Schisterman, Enrique F. (2020)
    Background Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed. Results Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (<18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p <0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes. Conclusions Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways.
  • Sivula, Mirka; Lassila, Riitta (2020)
  • Laakso, Sini; Myllykangas, Liisa; Hietaharju, Aki (2021)
    COVID-19-infektion neurologisista ilmentymistä kertynyt tieto on tapausselostusten ja -sarjojen hallitsemaa. Yleisimmät neurologiset ilmentymät ovat olleet haju- ja makuaistin muutokset. Aivoverenkiertohäiriöt, enkefalopatia ja immuunivälitteiset keskushermoston sairaudet tulevat usein esiin COVID-19-infektion komplikaatioina, mutta toisaalta Guillain-Barrén oireyhtymän osalta yhteys tähän infektioon kumottiin laajemmassa epidemiologisessa kohorttitutkimuksessa. Myös enkefaliitin, epileptisten kohtauksien, ääreishermoston sairauksien ja lihassairauksien on kuvattu liittyvän tähän infektioon. Neuropatologisissa tutkimuksissa tärkeimmät löydökset ovat olleet hypoksis-iskeeminen vaurio, verenvuodot ja epäspesifiset tulehdusmuutokset. Vielä odotellaan varmuutta siitä, aiheutuvatko kudosmuutokset viruksen invaasiosta aivoihin vai onko kyse epäsuorista muutoksista. Mekanismi SARS-CoV2-viruksen pääsylle aivokudokseen näyttäisi olevan olemassa. COVID-19-infektion jälkeisestä pitkittyneestä neurologisesta oireilusta tarvitaan lisää tutkimustietoa.
  • Haapakoski, Rita; Mathieu, Julia; Ebmeier, Klaus P.; Alenius, Harri; Kivimaki, Mika (2015)
    Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and Psychlnfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d = 0.54, p <0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d = 0.47, p <0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-alpha levels and major depression (d = 0.40, p = 0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1 beta levels and major depression (d = -0.05, p = 0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-alpha, interleukin-1 beta and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression. (C) 2015 The Authors. Published by Elsevier Inc.