Browsing by Subject "C-REACTIVE PROTEIN"

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  • Task Force Members; ESC Comm Practice Guidelines CPG; ESC Natl Cardiac Societies; Mach, Francois; Baigent, Colin; Taskinen, Marja-Riitta (2019)
  • Hungarian Pancreatic Study Grp; Farkas, Nelli; Hanak, Lilla; Miko, Alexandra; Sallinen, Ville; Hegyi, Peter (2019)
    Background: C-reactive protein level (CRP) and white blood cell count (WBC) have been variably used in clinical trials on acute pancreatitis (AP). We assessed their potential role. Methods: First, we investigated studies which have used CRP or WBC, to describe their current role in trials on AP. Second, we extracted the data of 1435 episodes of AP from our registry. CRP and WBC on admission, within 24 h from the onset of pain and their highest values were analyzed. Descriptive statistical tools as Kruskal-Wallis, Mann-Whitney U, Levene's F tests, Receiver Operating Characteristic (ROC) curve analysis and AUC (Area Under the Curve) with 95% confidence interval (CI) were performed. Results: Our literature review showed extreme variability of CRP used as an inclusion criterion or as a primary outcome or both in past and current trials on AP. In our cohort, CRP levels on admission poorly predicted mortality and severe cases of AP; AUC: 0.669 (CI:0.569-0.770); AUC:0.681 (CI: 0.601-0.761), respectively. CRP levels measured within 24 h from the onset of pain failed to predict mortality or severity; AUC: 0.741 (CI:0.627-0.854); AUC:0.690 (CI:0.586-0.793), respectively. The highest CRP during hospitalization had equally poor predictive accuracy for mortality and severity AUC:0.656 (CI:0.544-0.768); AUC:0.705 (CI:0.640-0.769) respectively. CRP within 24 h from the onset of pain used as an inclusion criterion markedly increased the combined event rate of mortality and severe AP (13% for CRP > 25 mg/l and 28% for CRP > 200 mg/l). Conclusion: CRP within 24 h from the onset of pain as an inclusion criterion elevates event rates and reduces the number of patients required in trials on AP.
  • Cremers, Eline M. P.; de Witte, Theo; de Wreede, Liesbeth; Eikema, Diderik-Jan; Koster, Linda; van Biezen, Anja; Finke, Jurgen; Socie, Gerard; Beelen, Dietrich; Maertens, Johan; Nagler, Arnon; Kobbe, Guido; Ziagkos, Dimitris; Itälä-Remes, Maija; Gedde-Dahl, Tobias; Sierra, Jorge; Niederwieser, Dietger; Ljungman, Per; Beguin, Yves; Ozkurt, Zubeyde Nur; Anagnostopoulos, Achilles; Jindra, Pavel; Robin, Marie; Kröger, Nicolaus (2019)
    Most myelodysplastic syndromes (MDS)-patients receive multiple red blood cell transfusions (RBCT). Transfusions may cause iron-related toxicity and mortality, influencing outcome after allogeneic HSCT. This prospective non-interventional study evaluated 222 MDS and CMML patients undergoing HSCT. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence (RI) at 36 months were 52%, 44%, 25%, and 31%, respectively. Age, percentage of marrow blasts and severe comorbidities impacted OS. RFS was significantly associated with RBCT burden prior to HSCT (HR: 1.7; p = .02). High ferritin levels had a significant negative impact on OS and RI, but no impact on NRM. Administration of iron chelation therapy prior to HSCT did not influence the outcome, but early iron reduction after HSCT (started before 6 months) improved RFS significantly after transplantation (56% in the control group vs. 90% in the treated group, respectively; p = .04). This study illustrates the impact of RBCT and related parameters on HSCT-outcome. Patients with an expected prolonged survival after transplantation may benefit from early iron reduction therapy after transplantation.
  • Gunnarsson, Ulf; Strigård, Karin; Edin, Sofia; Gkekas, Ioannis; Mustonen, Harri; Kaprio, Tuomas; Böckelman, Camilla; Hagström, Jaana; Palmqvist, Richard; Haglund, Caj (2020)
    Systemic inflammatory response in colorectal cancer (CRC) has been established as a prognostic factor for impaired cancer-specific survival, predominantly in patients with right-sided tumors. On the other hand, defective mismatch repair (dMMR) tumors, primarily located in the right colon, are known to have favorable survival and dense local immune infiltration. The aim of this study was to see if there is any form of relationship between these seemingly diverse entities.
  • White, James; Kivimaki, Mika; Jokela, Markus; Batty, G. David (2017)
    Elevated levels of inflammatory markers, such as C-reactive protein, are well documented in people with depression. Few studies have examined whether the association between inflammation and depression is symptom specific, and differs according to antidepressant treatment. Using data from the English Longitudinal Study of Ageing (N = 5909), cross-sectional analyses revealed a significant dose-response association between C-reactive protein and the symptoms of fatigue (P <0.001), restless sleep (P = 0.03), low energy (P = 0.02) and feeling depressed (P = 0.04), but not other symptoms. These associations were absent in users of anti-depressant medication. Our findings suggest the C-reactive protein depression association is symptom-specific and modified by antidepressant treatment. (C) 2016 Elsevier Inc. All rights reserved.
  • Mikkola, Tuija M.; von Bonsdorff, Mikaela B.; Salonen, Minna K.; Simonen, Mika; Pohjolainen, Pertti; Osmond, Clive; Perälä, Mia-Maria; Rantanen, Taina; Kajantie, Eero; Eriksson, Johan (2018)
    Background: This study assessed how different measures of body composition predict physical performance ten years later among older adults. Methods: The participants were 1076 men and women aged 57 to 70 years. Body mass index (BMI), waist circumference, and body composition (bioelectrical impedance analysis) were measured at baseline and physical performance (Senior Fitness Test) ten years later. Linear regression analyses were adjusted for age, education, smoking, duration of the follow-up and physical activity. Results: Greater BMI, waist circumference, fat mass, and percent body fat were associated with poorer physical performance in both sexes (standardized regression coefficient [beta] from -0.32 to -0.40, p <0.001). Lean mass to BMI ratio was positively associated with later physical performance (beta = 0.31 in men, beta = 0.30 in women, p <0.001). Fat-free mass index (lean mass/height(2)) in both sexes and lean mass in women were negatively associated with later physical performance. Lean mass residual after accounting for the effect of height and fat mass was not associated with physical performance. Conclusions: Among older adults, higher measures of adiposity predicted poorer physical performance ten years later whereas lean mass was associated with physical performance in a counterintuitive manner. The results can be used when appraising usefulness of body composition indicators for definition of sarcopenic obesity.
  • Kuusela, Pentti I; Saraswat, Mayank; Joenväärä, Sakari; Kaartinen, Johanna; Järvinen, Asko; Renkonen, Risto (2017)
    Blood culture is the primary diagnostic test performed in a suspicion of bloodstream infection to detect the presence of microorganisms and direct the treatment. However, blood culture is slow and time consuming method to detect blood stream infections or separate septic and/or bacteremic patients from others with less serious febrile disease. Plasma proteomics, despite its challenges, remains an important source for early biomarkers for systemic diseases and might show changes before direct evidence from bacteria can be obtained. We have performed a plasma proteomic analysis, simultaneously at the time of blood culture sampling from ten blood culture positive and ten blood culture negative patients, and quantified 172 proteins with two or more unique peptides. Principal components analysis, Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) and ROC curve analysis were performed to select protein(s) features which can classify the two groups of samples. We propose a number of candidates which qualify as potential biomarkers to select the blood culture positive cases from negative ones. Pathway analysis by two methods revealed complement activation, phagocytosis pathway and alterations in lipid metabolism as enriched pathways which are relevant for the condition. Data are available via ProteomeXchange with identifier PXD005022.
  • Jokela, Markus; García-Velázquez, Regina; Airaksinen, Jaakko; Gluschkoff, Kia; Kivimäki, Mika; Rosenström, Tom (2019)
    Background: Depression is a heterogeneous mental disorder with multiple symptoms, but only few studies have examined whether associations of risk factors with depression are symptom-specific. We examined whether chronic diseases and social risk factors (poverty, divorce, and perceived lack of emotional support) are differently associated with somatic and cognitive/affective symptoms of depression. Methods: Cross-sectional analyses were based on individual-level data from the 31,191 participants of six cross-sectional U.S. National Health and Nutrition Examination Surveys (NHANES) carried out between 2005 and 2016. Depressive symptoms were assessed using the 9-item Patient Health Questionnaire. Information on chronic diseases and social risk factors was self-reported by participants. Results: After adjustment for sex, age, race/ethnicity, and all the of other symptoms besides the outcome symptom, higher number of chronic diseases was independently related to fatigue, psychomotor retardation/agitation, and sleep problems in a dose-response pattern (range of odds ratios: 1.21 to 2.59). Except for concentration problems, social risk factors were associated with almost all of the cognitive/affective symptoms (range of odds ratios: 1.02 to 2.09) but only sporadically with somatic symptoms. Limitations: All measures were self-reported by the participants, which may have introduced bias to the associations. Cross-sectional data did not allow us to study temporal dynamics. Conclusions: Specific symptoms of depression may be useful in characterizing the heterogeneous etiology of depression with respect to somatic versus social risk factors.
  • Lim, Soo; Taskinen, Marja-Riitta; Boren, Jan (2019)
    Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low-grade inflammation in the liver. A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue and de novo lipogenesis can lead to NAFLD and insulin resistance. Thus, individuals with obesity, insulin resistance, and dyslipidaemia are at the greatest risk of developing NAFLD. Conversely, NAFLD is a phenotype of cardiometabolic syndrome. Notably, researchers have discovered a close association between NAFLD and impaired glucose metabolism and focused on the role of NAFLD in the development of type 2 diabetes. Moreover, recent studies provide substantial evidence for an association between NAFLD and atherosclerosis and cardiometabolic disorders. Even if NAFLD can progress into severe liver disorders including nonalcoholic steatohepatitis (NASH) and cirrhosis, the majority of subjects with NAFLD die from cardiovascular disease eventually. In this review, we propose a potential pathological link between NAFLD/NASH and cardiometabolic syndrome. The potential factors that can play a pivotal role in this link, such as inflammation, insulin resistance, alteration in lipid metabolism, oxidative stress, genetic predisposition, and gut microbiota are discussed.
  • Di Saverio, Salomone; Podda, Mauro; De Simone, Belinda; Ceresoli, Marco; Augustin, Goran; Gori, Alice; Boermeester, Marja; Sartelli, Massimo; Coccolini, Federico; Tarasconi, Antonio; Angelis, Nicola de'; Weber, Dieter G.; Tolonen, Matti; Birindelli, Arianna; Biffl, Walter; Moore, Ernest E.; Kelly, Michael; Soreide, Kjetil; Kashuk, Jeffry; Ten Broek, Richard; Gomes, Carlos Augusto; Sugrue, Michael; Davies, Richard Justin; Damaskos, Dimitrios; Leppäniemi, Ari; Kirkpatrick, Andrew; Peitzman, Andrew B.; Fraga, Gustavo P.; Maier, Ronald V.; Coimbra, Raul; Chiarugi, Massimo; Sganga, Gabriele; Pisanu, Adolfo; Angelis, Gian Luigi de'; Tan, Edward; Van Goor, Harry; Pata, Francesco; Di Carlo, Isidoro; Chiara, Osvaldo; Litvin, Andrey; Campanile, Fabio C.; Sakakushev, Boris; Tomadze, Gia; Demetrashvili, Zaza; Latifi, Rifat; Abu-Zidan, Fakri; Romeo, Oreste; Segovia-Lohse, Helmut; Baiocchi, Gianluca; Costa, David; Rizoli, Sandro; Balogh, Zsolt J.; Bendinelli, Cino; Scalea, Thomas; Ivatury, Rao; Velmahos, George; Andersson, Roland; Kluger, Yoram; Ansaloni, Luca; Catena, Fausto (2020)
    Background and aims Acute appendicitis (AA) is among the most common causes of acute abdominal pain. Diagnosis of AA is still challenging and some controversies on its management are still present among different settings and practice patterns worldwide. In July 2015, the World Society of Emergency Surgery (WSES) organized in Jerusalem the first consensus conference on the diagnosis and treatment of AA in adult patients with the intention of producing evidence-based guidelines. An updated consensus conference took place in Nijemegen in June 2019 and the guidelines have now been updated in order to provide evidence-based statements and recommendations in keeping with varying clinical practice: use of clinical scores and imaging in diagnosing AA, indications and timing for surgery, use of non-operative management and antibiotics, laparoscopy and surgical techniques, intra-operative scoring, and peri-operative antibiotic therapy. Methods This executive manuscript summarizes the WSES guidelines for the diagnosis and treatment of AA. Literature search has been updated up to 2019 and statements and recommendations have been developed according to the GRADE methodology. The statements were voted, eventually modified, and finally approved by the participants to the consensus conference and by the board of co-authors, using a Delphi methodology for voting whenever there was controversy on a statement or a recommendation. Several tables highlighting the research topics and questions, search syntaxes, and the statements and the WSES evidence-based recommendations are provided. Finally, two different practical clinical algorithms are provided in the form of a flow chart for both adults and pediatric (<16 years old) patients. Conclusions The 2020 WSES guidelines on AA aim to provide updated evidence-based statements and recommendations on each of the following topics: (1) diagnosis, (2) non-operative management for uncomplicated AA, (3) timing of appendectomy and in-hospital delay, (4) surgical treatment, (5) intra-operative grading of AA, (6) ,management of perforated AA with phlegmon or abscess, and (7) peri-operative antibiotic therapy.
  • Wang, Qin; Wurtz, Peter; Auro, Kirsi; Morin-Papunen, Laure; Kangas, Antti J.; Soininen, Pasi; Tiainen, Mika; Tynkkynen, Tuulia; Joensuu, Anni; Havulinna, Aki S.; Aalto, Kristiina; Salmi, Marko; Blankenberg, Stefan; Zeller, Tanja; Viikari, Jorma; Kahonen, Mika; Lehtimaki, Terho; Salomaa, Veikko; Jalkanen, Sirpa; Jarvelin, Marjo-Riitta; Perola, Markus; Raitakari, Olli T.; Lawlor, Debbie A.; Kettunen, Johannes; Ala-Korpela, Mika (2016)
    Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood. Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24-49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception. Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery. Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.
  • Auvinen, Piritta; Mäntyselkä, Pekka; Koponen, Hannu; Kautiainen, Hannu; Korniloff, Katariina; Ahonen, Tiina; Vanhala, Mauno (2018)
    Background: Restless legs syndrome is a sensorimotor disorder associated with several mental illnesses particularly depression. Methods: A cross-sectional study of primary care patients. The prevalence of restless legs symptoms was studied in 706 patients with depressive symptoms and 426 controls without a psychiatric diagnosis by using a structured questionnaire. The depressive symptoms were evaluated with the BDI and the psychiatric diagnosis was confirmed by means of a diagnostic interview (M.I.N.I.). The subjects with elevated depressive symptoms were divided into two groups subjects with depressive symptoms with and without clinical depression. Results: The prevalence of restless legs symptoms was 24.8% in the controls, 50.0% in the patients with clinical depression and 42.4% in the patients with depressive symptoms. CRP value was significantly higher (p =.003) in the clinically depressed patients than in the other groups. There was a higher concentration of TNF-alpha in the subjects with restless legs symptoms (7.4 ng/l +/- 3.2) compared with the subjects without symptoms (6.7 ng/1 +/- 2.3)(p Conclusions: TNF-alpha level was associated with restless legs symptoms only among subjects with depressive symptoms whether they had clinical depression or not. We suggest that TNF-alpha could be an underlying factor between restless legs symptoms and comorbidities.
  • Zannas, Anthony S.; Jia, Meiwen; Hafner, Kathrin; Baumert, Jens; Wiechmann, Tobias; Pape, Julius C.; Arloth, Janine; Ködel, Maik; Martinelli, Silvia; Roitman, Maria; Roeh, Simone; Haehle, Andreas; Emeny, Rebecca T.; Iurato, Stella; Carrillo-Roa, Tania; Lahti, Jari; Räikkönen, Katri; Eriksson, Johan G.; Drake, Amanda J.; Waldenberger, Melanie; Wahl, Simone; Kunze, Sonja; Lucae, Susanne; Bradley, Bekh; Gieger, Christian; Hausch, Felix; Smith, Alicia K.; Ressler, Kerry J.; Mueller-Myhsok, Bertram; Ladwig, Karl-Heinz; Rein, Theo; Gassen, Nils C.; Binder, Elisabeth B. (2019)
    Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.
  • Nurmi, Katariina; Virkanen, Juhani; Rajamaki, Kristiina; Niemi, Katri; Kovanen, Petri T.; Eklund, Kari K. (2013)
  • Lindgren, Maija; Holm, Minna; Markkula, Niina; Härkänen, Tommi; Dickerson, Faith; Yolken, Robert H.; Suvisaari, Jaana (2020)
    Common infectious agents, such as Toxoplasma gondii (T. gondii) and several human herpes viruses, have been linked to increased risk of self-harm. The aim of this study was to investigate the associations between self-harm and seropositivity to T. gondii, Epstein-Barr virus (EBV), Herpes Simplex virus Type 1 (HSV-1), and Cytomegalovirus (CMV). IgM and IgG antibodies to these infections were measured in the Health 2000 project nationally representative of the whole Finnish adult population, and 6250 participants, age 30 and over, were followed for 15 years via registers. In addition, lifetime suicidal ideation and suicide attempts based on medical records and interview were assessed within a subsample of 694 participants screened to a substudy for possible psychotic symptoms or as controls. Among the 6250 participants, 14 individuals died of suicide and an additional 4 individuals had a diagnosis of intentional self-harm during follow-up. Serological evidence of lifetime or acute infections was not found to be associated with these suicidal outcomes. However, in the subsample, those seropositive for CMV had fewer suicide attempts compared to those seronegative, adjusting for gender, age, educational level, childhood family size, regional residence, CRP, and screen status (OR for multiple attempts = 0.40, 95% confidence interval 0.20-0.83, p = 0.014). To conclude, common infections were not associated with risk of death by suicide or with self-harm diagnoses at a 15-year follow-up in the general population sample. Our finding of an increased number of suicide attempts among persons seronegative for CMV calls for further research.
  • Robinson, Rachel; Lahti-Pulkkinen, Marius; Heinonen, Kati; Reynolds, Rebecca M.; Räikkönen, Katri (2019)
    BACKGROUND: Maternal depression complicates a large proportion of pregnancies. Current evidence shows numerous harmful effects on the offspring. Reviews, which include depression, concluded that stress has harmful effects on the offspring's outcomes neuro-cognitive development, temperament traits, and mental disorders. OBJECTIVE: This mini review of recent studies, sought to narrow the scope of exposure and identify studies specifically assessing prenatal depression and offspring neuropsychiatric outcomes. STUDY ELIGIBILITY CRITERIA: The review included longitudinal, cohort, cross-sectional, clinical, quasi-experimental, epidemiological, or intervention study designs published in English from 2014 to 2018. PARTICIPANTS: Study populations included mother-child dyads, mother-father-child triads, mother-alternative caregiver-child triads, and family studies utilizing sibling comparisons. METHODS: We searched PubMED and Web of Science. Study inclusion and data extraction were based on standardized templates. The quality of evidence was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: Thirteen studies examining neuropsychiatric outcomes were included. We judged the evidence to be moderate to high quality. CONCLUSIONS: Our review supports that maternal prenatal depression is associated with neuropsychiatric adversities in children.
  • Meri, Seppo; Haapasalo, Karita (2020)
    Complement-mediated inflammation or dysregulation in lipid metabolism are associated with the pathogenesis of several diseases. These include age-related macular degeneration (AMD), C3 glomerulonephritis (C3GN), dense deposit disease (DDD), atherosclerosis, and Alzheimer's disease (AD). In all these diseases, formation of characteristic lipid-rich deposits is evident. Here, we will discuss molecular mechanisms whereby dysfunction of complement, and especially of its key regulator factor H, could be involved in lipid accumulation and related inflammation. The genetic associations to factor H polymorphisms, the role of factor H in the resolution of inflammation in lipid-rich deposits, modification of macrophage functions, and complement-mediated clearance of apoptotic and damaged cells indicate that the function of factor H is crucial in limiting inflammation in these diseases.
  • Mahlman, Mari; Karjalainen, Minna K.; Huusko, Johanna M.; Andersson, Sture; Kari, M. Anneli; Tammela, Outi K. T.; Sankilampi, Ulla; Lehtonen, Liisa; Marttila, Riitta H.; Bassler, Dirk; Poets, Christian F.; Lacaze-Masmonteil, Thierry; Danan, Claude; Delacourt, Christophe; Palotie, Aarno; Muglia, Louis J.; Lavoie, Pascal M.; Hadchouel, Alice; Ramet, Mika; Hallman, Mikko (2017)
    Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [ OR] 3.2, p = 3.4 x 10(-6)). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 x 10(-4)) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 x 10(-5)), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.
  • Ahluwalia, Tarunveer S; Prins, Bram P; Abdollahi, Mohammadreza; Armstrong, Nicola J; Aslibekyan, Stella; Bain, Lisa; Jefferis, Barbara; Baumert, Jens; Beekman, Marian; Ben-Shlomo, Yoav; Bis, Joshua C; Mitchell, Braxton D; de Geus, Eco; Delgado, Graciela E; Marek, Diana; Eriksson, Joel; Kajantie, Eero; Kanoni, Stavroula; Kemp, John P; Lu, Chen; Marioni, Riccardo E; McLachlan, Stela; Milaneschi, Yuri; Nolte, Ilja M; Petrelis, Alexandros M; Porcu, Eleonora; Sabater-Lleal, Maria; Naderi, Elnaz; Seppälä, Ilkka; Shah, Tina; Singhal, Gaurav; Standl, Marie; Teumer, Alexander; Thalamuthu, Anbupalam; Thiering, Elisabeth; Trompet, Stella; Ballantyne, Christie M; Benjamin, Emelia J; Casas, Juan P; Toben, Catherine; Dedoussis, George; Deelen, Joris; Durda, Peter; Engmann, Jorgen; Feitosa, Mary F; Grallert, Harald; Hammarstedt, Ann; Harris, Sarah E; Homuth, Georg; Hottenga, Jouke-Jan; Jalkanen, Sirpa; Jamshidi, Yalda; Jawahar, Magdalene C; Jess, Tine; Kivimaki, Mika; Kleber, Marcus E; Lahti, Jari; Liu, Yongmei; Marques-Vidal, Pedro; Mellström, Dan; Mooijaart, Simon P; Müller-Nurasyid, Martina; Penninx, Brenda; Revez, Joana A; Rossing, Peter; Räikkönen, Katri; Sattar, Naveed; Scharnagl, Hubert; Sennblad, Bengt; Silveira, Angela; Pourcain, Beate St; Timpson, Nicholas J; Trollor, Julian; Group, CHARGE Inflammation Working; van Dongen, Jenny; Van Heemst, Diana; Visvikis-Siest, Sophie; Vollenweider, Peter; Völker, Uwe; Waldenberger, Melanie; Willemsen, Gonneke; Zabaneh, Delilah; Morris, Richard W; Arnett, Donna K; Baune, Bernhard T; Boomsma, Dorret I; Chang, Yen-Pei C; Deary, Ian J; Deloukas, Panos; Eriksson, Johan G; Evans, David M; Ferreira, Manuel A; Gaunt, Tom; Gudnason, Vilmundur; Hamsten, Anders; Heinrich, Joachim; Hingorani, Aroon; Humphries, Steve E; Jukema, J Wouter; Koenig, Wolfgang; Kumari, Meena; Kutalik, Zoltan; Lawlor, Deborah A; Lehtimäki, Terho; März, Winfried; Mather, Karen A; Naitza, Silvia; Nauck, Matthias; Ohlsson, Claes; Price, Jackie F; Raitakari, Olli; Rice, Ken; Sachdev, Perminder S; Slagboom, Eline; Sørensen, Thorkild I A; Spector, Tim; Stacey, David; Stathopoulou, Maria G; Tanaka, Toshiko; Wannamethee, S Goya; Whincup, Peter; Rotter, Jerome I; Dehghan, Abbas; Boerwinkle, Eric; Psaty, Bruce M; Snieder, Harold; Alizadeh, Behrooz Z (2021)
    Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (n(discovery)=52654 and n(replication)=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
  • Murphy, Neil; Ward, Heather A.; Jenab, Mazda; Rothwell, Joseph A.; Boutron-Ruault, Marie-Christine; Carbonnel, Franck; Kvaskoff, Marina; Kaaks, Rudolf; Kuehn, Tilman; Boeing, Heiner; Aleksandrova, Krasimira; Weiderpass, Elisabete; Skeie, Guri; Borch, Kristin Benjaminsen; Tjonneland, Anne; Kyro, Cecilie; Overvad, Kim; Dahm, Christina C.; Jakszyn, Paula; Sanchez, Maria-Jose; Gil, Leire; Huerta, Jose M.; Barricarte, Aurelio; Ramon Quiros, J.; Khaw, Kay-Tee; Wareham, Nick; Bradbury, Kathryn E.; Trichopoulou, Antonia; La Vecchia, Carlo; Karakatsani, Anna; Palli, Domenico; Grioni, Sara; Tumino, Rosario; Fasanelli, Francesca; Panico, Salvatore; Bueno-de-Mesquita, Bas; Peeters, Petra H.; Gylling, Bjorn; Myte, Robin; Jirstrom, Karin; Berntsson, Jonna; Xue, Xiaonan; Riboli, Elio; Cross, Amanda J.; Gunter, Marc J. (2019)
    BACKGROUND & AIMS: Colorectal cancer located at different anatomical subsites may have distinct etiologies and risk factors. Previous studies that have examined this hypothesis have yielded inconsistent results, possibly because most studies have been of insufficient size to identify heterogeneous associations with precision. METHODS: In the European Prospective Investigation into Cancer and Nutrition study, we used multivariable joint Cox proportional hazards models, which accounted for tumors at different anatomical sites (proximal colon, distal colon, and rectum) as competing risks, to examine the relationships between 14 established/suspected lifestyle, anthropometric, and reproductive/menstrual risk factors with colorectal cancer risk. Heterogeneity across sites was tested using Wald tests. RESULTS: After a median of 14.9 years of follow-up of 521,330 men and women, 6291 colorectal cancer cases occurred. Physical activity was related inversely to proximal colon and distal colon cancer, but not to rectal cancer (P heterogeneity = .03). Height was associated positively with proximal and distal colon cancer only, but not rectal cancer (P heterogeneity = .0001). For men, but not women, heterogeneous relationships were observed for body mass index (P heterogeneity = .008) and waist circumference (P heterogeneity = .03), with weaker positive associations found for rectal cancer, compared with proximal and distal colon cancer. Current smoking was associated with a greater risk of rectal and proximal colon cancer, but not distal colon cancer (P heterogeneity = .05). No heterogeneity by anatomical site was found for alcohol consumption, diabetes, nonsteroidal anti-inflammatory drug use, and reproductive/menstrual factors. CONCLUSIONS: The relationships between physical activity, anthropometry, and smoking with colorectal cancer risk differed by subsite, supporting the hypothesis that tumors in different anatomical regions may have distinct etiologies.