Circulating inflammatory cytokines and risk of five cancers : a Mendelian randomization analysis

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.Peer reviewe

Prevalence and determinants of sex-specific dietary supplement use in a greek cohort

We describe the profile of dietary supplement use and its correlates in the Epirus Health Study cohort, which consists of 1237 adults (60.5% women) residing in urban north-west Greece. The association between dietary supplement use and demographic characteristics, lifestyle behaviors, personal medical history and clinical measurements was assessed using logistic regression models, separately for women and men. The overall prevalence of dietary supplement use was 31.4%, and it was higher in women (37.3%) compared to men (22.4%; p-value = 4.2−08). Based on multivariable logistic regression models, dietary supplement use in women was associated with age (positively until middle-age and slightly negatively afterwards), the presence of a chronic health condition (OR = 1.71; 95% CI, 1.18–2.46), lost/removed teeth (OR = 0.52; 95% CI, 0.35–0.78) and diastolic blood pressure (OR per 5 mmHg increase =0.84; 95% CI, 0.73–0.96); body mass index and worse general health status were borderline inversely associated. In men, dietary supplement use was positively associated with being employed (OR = 2.53; 95% CI, 1.21–5.29). A considerable proportion of our sample used dietary supplements, and the associated factors differed between women and men

The interplay between inflammatory cytokines and cardiometabolic disease: bi-directional mendelian randomisation study

Objective To leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets. Design Bi-directional Mendelian randomisation study. Setting Genome-wide association studies from three Finnish cohorts (Northern Finland Birth Cohort 1966, Young Finns Study, or FINRISK study), and genetic association summary statistics pooled from observational studies for expression quantitative trait loci and cardiometabolic traits. Participants Data for 47 circulating cytokines in 13 365 individuals from genome-wide association studies, summary statistic data for up to 21 735 individuals on circulating cytokines, summary statistic gene expression data across 49 tissues in 838 individuals, and summary statistic data for up to 1 320 016 individuals on cardiometabolic traits. Interventions Relations between circulating cytokines and cardiovascular, anthropometric, lipid, or glycaemic traits (coronary artery disease, stroke, type 2 diabetes mellitus, body mass index, waist circumference, waist to hip ratio, systolic blood pressure, glycated haemoglobin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, triglycerides, C reactive protein, glucose, fasting insulin, and lifetime smoking). Main outcome methods Genetic instrumental variables that are biologically plausible for the circulating cytokines were generated. The effects of cardiometabolic risk factors on concentrations of circulating cytokines, circulating cytokines on other circulating cytokines, and circulating cytokines on cardiometabolic outcomes were investigated. Results Genetic evidence (mendelian randomisation P0.5) suggested that coronary artery disease risk is increased by higher concentrations of circulating tumour necrosis factor related apoptosis-inducing ligand (TRAIL), interleukin-1 receptor antagonist (IL1RA), and macrophage colony-stimulating factor (MCSF). Conclusion This study offers insight into inflammatory mediators of cardiometabolic risk factors, cytokine signalling cascades, and effects of circulating cytokines on different cardiometabolic outcomes

A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Geneenvironment interactions (G x E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G x E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G x E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G x E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant GxBMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer

Διερεύνηση των βιολογικών μηχανισμών οι οποίοι συνδέουν διατροφικούς παράγοντες με τον καρκίνο του στομάχου και του παχέος εντέρου με την εφαρμογή μετά-ανάλυσης των σχετικών μελετών

Gastric cancer (GC) and Colorectal cancer (CRC), being among the five most common cancers worldwide and accounting for more than 17% of all incident cancer cases, represent major public health concerns. Several dietary exposures have been associated with GC and CRC in epidemiological studies, however, for some exposures results are conflicting, and even for the established diet-related risk factors the underlying mechanisms are not fully understood. Understanding the pathophysiological pathways linking diet to cancer is key in establishing causality and may aid in the development of targeted interventions for susceptible individuals. The present study aims to investigate the biological mechanisms linking diet to GC and CRC. We conducted an umbrella review using the bibliographic databases of MEDLINE (assessed via PubMed) and Elsevier’s Scopus, and a nutrient-wide association study in the European cohort study of EPIC (European Prospective Investigation into Cancer and Nutrition) with replication in an independent European cohort, the NLCS (Netherlands Cohort Study), to investigate the associations of diet-related exposures in relation to risk of GC and CRC, respectively. We mapped the mechanistic evidence linking diet to GC and CRC in the published literature, via a text-mining literature review and pathway over-representation analysis. Utilizing modern molecular epidemiological analytical approaches, namely a Mendelian randomization mediation analysis and a Genome-wide interaction study (GWIS), we investigated mechanisms linking excess body weight [captured using the Body Mass Index (BMI)], and folate, to CRC risk. Our findings confirmed the positive association of increased salt-preserved food consumption and GC risk and strengthen the evidence for a positive association between heavy alcohol consumption and risk of GC and CRC. Furthermore, the inverse association between dairy and CRC risk, and the positive association of excess body weight and gastric cardia cancer (GCC) and CRC risk, were confirmed. A large body of mechanistic studies, covering a broad spectrum of biological pathways, is focused on established cancer risk factors (such as adiposity, and fruit and vegetable consumption) and related dietary bioactive constituents (such as phytochemicals). We found that the effect of BMI on CRC risk is partly mediated through insulin like growth factor (IGF-1). Finally, the GWIS showed that genetic variation in locus 3p25.2 [in the region of Synapsin II (SYN2)/tissue inhibitor of metalloproteinase 4 (TIMP4)] might modify the association of folate with CRC risk. Maintaining a normal body weight, and adopting healthy dietary choices, in combination with smoking abstinence and regular physical activity reduces the risk of developing GC and CRC. A potential implication of IGF-1 and SYN2/TIMP4, in the associations of BMI and folate, respectively, on CRC risk, warrant further experimental investigation.Ο καρκίνος του στομάχου και του παχέος εντέρου (ΠΕ) είναι ανάμεσα στους 5 συχνότερους καρκίνους παγκοσμίως και μαζί καταλαμβάνουν ποσοστό υψηλότερο του 17% των νέων περιστατικών καρκίνου, ανά έτος. Διατροφικές εκθέσεις έχουν συσχετιστεί με αυτούς τους καρκίνους μέσα από επιδημιολογικές μελέτες, ωστόσο για ορισμένες εξ’ αυτών τα αποτελέσματα είναι αντικρουόμενα, ενώ ακόμα και για τους καθιερωμένους διατροφικούς παράγοντες κινδύνου, οι μηχανισμοί που έχουν προταθεί δεν έχουν τεκμηριωθεί επαρκώς. Σκοπός μας είναι η διερεύνηση των βιολογικών μηχανισμών οι οποίοι συνδέουν διατροφικούς παράγοντες με τον καρκίνο του στομάχου και του ΠΕ προκειμένου να ενισχυθεί η γνώση μας για την ύπαρξη αιτιακών σχέσεων. Πραγματοποιήσαμε μια ανασκόπηση τύπου ομπρέλας χρησιμοποιώντας τις βιβλιογραφικές βάσεις των MEDLINE (PubMed) και Elsevier (Scopus), και μια ανάλυση συσχέτισης ευρείας κλίμακας διατροφικών παραγόντων στην ευρωπαϊκή μελέτη κοόρτης της EPIC με επικύρωση των συσχετίσεων σε μια ανεξάρτητη κοόρτη (την NLCS), προκειμένου να διερευνήσουμε τη συσχέτιση διατροφικών παραγόντων με τον καρκίνο του στομάχου, και του ΠΕ, αντίστοιχα. Πραγματοποιήσαμε χαρτογράφηση των μηχανιστικών μελετών στη βιβλιογραφία με τη χρήση τεχνικών αλίευσης δεδομένων κειμένου, σε μια ανασκόπηση μηχανισμών. Χρησιμοποιώντας αναλυτικές τεχνικές σύγχρονης επιδημιολογίας, όπως η Μεντελιανή τυχαιοποίηση και ανάλυση αλληλεπίδρασης σε ευρυγονιδιακή κλίμακα, διερευνήσαμε τους μηχανισμούς που συνδέουν το αυξημένο σωματικό λίπος (όπως αποτυπώνεται με τη χρήση του δείκτη μάζας σώματος) και την πρόσληψη φολικού οξέος με τον καρκίνο του ΠΕ. Τα ευρήματα που προέκυψαν επιβεβαιώνουν τη θετική σχέση της αυξημένης πρόσληψης αλατιού μέσω τροφών με τον κίνδυνο εμφάνισης καρκίνου στον στόμαχο, και ενισχύουν τη γνώση μας για την ύπαρξη θετικής σχέσης μεταξύ της υψηλής κατανάλωση αλκοόλ με τον κίνδυνο εμφάνισης καρκίνου στον στόμαχο και το ΠΕ. Επιπλέον, επιβεβαιώνεται η αντίστροφη συσχέτιση που αφορά την κατανάλωση γαλακτοκομικών, και η θετική συσχέτιση του αυξημένου σωματικού λίπους με τον καρκίνο της καρδιακής μοίρας του στομάχου και του ΠΕ. Η ανασκόπηση μηχανισμών ανέδειξε την παρουσία μεγάλου όγκου μηχανιστικών μελετών, που καλύπτουν εύρος μοριακών μονοπατιών για εκθέσεις όπως η παχυσαρκία, τα φρούτα και λαχανικά, και σχετικές βιοδραστικές ενώσεις. Βρέθηκε σημαντική διαμεσολάβηση του ινσουλινόμορφου αυξητικού παράγοντα (IGF-1) στην σχέση του αυξημένου σωματικού λίπους με τον καρκίνο του ΠΕ. Επιπλέον, αναδείχθηκαν γενετικοί πολυμορφισμοί στην χρωμοσωμική περιοχή 3p25.2 [εγγύς του γονιδίου της Synapsin II (SYN2)/tissue inhibitor of metalloproteinase 4 (TIMP4)] ως τροποποιητικοί παράγοντες στην σχέση του φολικού οξέος με τον καρκίνο του ΠΕ. Διατηρώντας το σωματικό βάρος σε φυσιολογικά επίπεδα, και υιοθετώντας υγιεινές διατροφικές επιλογές σε συνδυασμό με σωματική άσκηση και αποχή από το κάπνισμα μειώνουν σημαντικά τον κίνδυνο εμφάνισης καρκίνου του ΠΕ και του στομάχου. Τα ευρήματα που αφορούν στο ρόλο της IGF-1 και της SYN2/TIMP4, στην σχέση της παχυσαρκίας και του φολικού οξέος, αντίστοιχα, με τον καρκίνο του ΠΕ, χρήζουν περεταίρω διερεύνησης μέσα από πειραματικές μελέτες και την αξιοποίηση δεδομένων ωμικής υψηλής ανάλυσης

Diet and Risk of Gastric Cancer: An Umbrella Review

Several dietary exposures have been associated with gastric cancer (GC), but the associations are often heterogenous and may be afflicted by inherent biases. In the context of an Umbrella Review (UR), we provide an overview and a critical evaluation of the strength and quality, and evidence classification of the associations of diet-related exposures in relation to the risk of GC. We searched PubMed and Scopus for eligible meta-analyses of observational studies published in English from inception to 12 December 2021, and for any identified association, we applied robust epidemiological validity evaluation criteria and individual study quality assessment using AMSTAR. We screened 3846 titles/abstracts and assessed 501 full articles for eligibility, of which 49 were included in the analysis, investigating 147 unique exposures in relation to GC, cardia (GCC) or non-cardia (GNCC) cancer. Supported by suggestive evidence, positive associations were found comparing the highest vs. lowest categories for: heavy (>42 g/day) alcohol consumption (Relative Risk (RR) = 1.42, 95% Confidence Interval (CI): 1.20–1.67), salted fish consumption (RR = 1.56, 95% CI:1.30–1.87) and waist circumference (RR = 1.48, 95% CI:1.24–1.78) and an inverse association for the healthy lifestyle index (RR = 0.60, 95% CI:0.48–0.74) in relation to GC. Additionally, a positive association was found comparing obese individuals (Body Mass Index (BMI) ≥ 30) to normal-weight individuals (BMI: 18.5–25) (RR = 1.82, 95% CI:1.32–2.49) in relation to GCC. Most of the meta-analyses were of medium-to-high quality (median items: 7.0, interquartile range: 6–9). Maintaining a normal body weight and adopting healthy dietary choices, in particular, limiting the consumption of salt-preserved foods and alcohol, can reduce the risk of gastric cancer

Non-Vitamin K Oral Anticoagulants in Adults with Congenital Heart Disease: A Systematic Review

Adults with congenital heart disease (ACHD) experience more thromboembolic complications than the general population. We systematically searched and critically appraised all studies on the safety and efficacy of non-vitamin-K oral anticoagulants (NOACs) in adult patients with various forms of congenital heart disease. PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) were used, with duplicate extraction of data and risk of bias assessment. The Newcastle-Ottawa quality assessment scale was used to assess study quality. Three studies fulfilled the inclusion criteria and were analyzed. The total number of participants was 766, with a total follow-up of 923 patient-years. The majority of patients (77%) received a NOAC for atrial arrhythmias, while the remainder were prescribed NOACs for secondary (19%) or primary (4%) thromboprophylaxis. The annual rate of thromboembolic and major bleeding events was low: 0.98% (95% CI: 0.51–1.86) and 1.74% (95% CI: 0.86–3.49) respectively. In Fontan patients, the annual rate of thromboembolic and major bleeding events was 3.13% (95% CI: 1.18–8.03) and 3.17% (95% CI: 0.15–41.39) respectively. NOACs appear safe and effective in ACHD without mechanical prostheses. Additional studies are, however, needed to confirm their efficacy in complex ACHD, especially those with a Fontan-type circulation