Μελέτη Μεντελιανής Τυχαιοποίησης για τη συσχέτιση διατροφικών χαρακτηριστικών με τον καρκίνο παχέος εντέρου

Εισαγωγή: Ο καρκίνος του παχέος εντέρου είναι ο τρίτος πιο διαδεδομένος καρκίνος παγκοσμίως απαριθμώντας πάνω από 1.2 εκατομμύρια νέες περιπτώσεις και 600.000 θανάτους ανά έτος. Ορισμένα χαρακτηριστικά σχετιζόμενα με τη διατροφή είναι γνωστοί παράγοντες κινδύνου για τον καρκίνο του παχέος εντέρου ενώ για την πλειοψηφία των διατροφικών παραγόντων, οι ενδείξεις ήταν είτε ασαφείς είτε περιορισμένες. Τα περισσότερα στοιχεία σχετικά με τη διατροφή και τον κίνδυνο ανάπτυξης καρκίνου προκύπτουν από μελέτες παρατήρησης. Σκοπός της παρούσας μελέτης είναι να ξεπεραστούν οι περιορισμοί αυτών των μελετών με τη χρήση της μεθόδου της Μενδελιανής τυχαιοποίησης. Εκτιμήθηκαν συσχετίσεις μεταξύ των γενετικά καθορισμένων προσλήψεων διατροφικών παραγόντων και του κινδύνου ανάπτυξης καρκίνου του παχέος εντέρου. Διεξήχθησαν αναλύσεις για τους ακόλουθους διατροφικούς παράγοντες: δημητριακά, φρέσκα φρούτα, επεξεργασμένο κρέας, πουλερικά, λιπαρά ψάρια, μη λιπαρά ψάρια, τυρί, τσάι και πράσινο τσάι. Μέθοδος: Πραγματοποιήθηκε μελέτη Μενδελιανής τυχαιοποίησης δύο δειγμάτων με τη χρήση περιληπτικών δεδομένων. Τα δεδομένα για τη σχέση των SNPs με τον καρκίνο του παχέος εντέρου αντλήθηκαν από 58,221 ασθενείς και 67,694 μάρτυρες από τη GECCO. Οι διατροφικοί παράγοντες επιλέχθηκαν από το World Cancer Research Fund (WCRF) Continuous Update Project (CUP) και τα περιληπτικά δεδομένα για τη σχέση τους με τα SNPs προήλθαν από GWAS της UK Biobank. Εφαρμόστηκε η μέθοδος Inverse Variance Weighted (IVW) για την εκτίμηση της αιτιακής σχέσης και πραγματοποιήθηκαν αναλύσεις ευαισθησίας (simple median, weighted median, MR-Egger, weighted mode, MR-PRESSO) για τον έλεγχο των παραδοχών της Μενδελιανής τυχαιοποίησης. Επιπρόσθετα, διεξήχθησαν αναλύσεις ανά υπότυπο του καρκίνου του παχέος εντέρου (κόλον, δεξί κόλον, αριστερό κόλον και ορθό). Αποτελέσματα: Η γενετικά καθορισμένη κατανάλωση λιπαρών ψαριών συσχετίστηκε με 27% χαμηλότερο κίνδυνο ανάπτυξης καρκίνου του παχέος εντέρου (Odds Ratio [OR]=0.73, 95% Διάστημα Εμπιστοσύνης [ΔΕ]=(0.58-0.92)), 30% χαμηλότερο κίνδυνο ανάπτυξης καρκίνου του κόλου (OR=0.70, 95% ΔΕ=(0.54-0.91)) και 37% χαμηλότερο κίνδυνο ανάπτυξης καρκίνου του αριστερού κόλου (OR=0.63, 95% ΔΕ=(0.46-0.85)). Επίσης, παρατηρήθηκε προστατευτική επίδραση της γενετικά καθορισμένης κατανάλωσης δημητριακών στον καρκίνου του ορθού (OR=0.59, 95% ΔΕ=(0.38-0.89)), ενώ οριακής στατιστικής σημαντικότητας προστατευτική συσχέτιση παρατηρήθηκε για τον ολικό καρκίνο παχέος εντέρου (OR=0.75, 95% ΔΕ=(0.55-1.01)). Προστατευτική επίδραση παρατηρήθηκε και για τη γενετικά καθορισμένη κατανάλωση φρέσκων φρούτων με τον καρκίνο του αριστερού κόλου (OR=0.58, 95% ΔΕ=(0.37-0.89)) χωρίς όμως να ενισχύεται από τις εκτιμήσεις των αναλύσεων ευαισθησίας. Δεν παρατηρήθηκε συσχέτιση των υπόλοιπων διατροφικών παραγόντων με τον καρκίνο του παχέος εντέρου. Συμπεράσματα: Τα ευρήματα έδειξαν πιθανή προστατευτική επίδραση των λιπαρών ψαριών στον ολικό καρκίνο του παχέος εντέρου, το ολικό κόλον και το αριστερό κόλον και ήπια προστατευτική των δημητριακών με τον ολικό καρκίνο του παχέος εντέρου και τον καρκίνο του ορθού. Παρόλα αυτά, δεν μπορούμε να αποφανθούμε με σιγουριά αιτιότητα λόγω πιθανής ύπαρξης πλειοτροπίας. Περαιτέρω μελέτες πρέπει να πραγματοποιηθούν στο μέλλον ώστε να επιβεβαιωθούν αυτά τα ευρήματα και να καταλήξουν σε στιβαρά αποτελέσματα.Background: Colorectal cancer is the third most common type of cancer worldwide with over one million new cases and 600,000 deaths each year. Several nutrition-related characteristics are well-established risk factors of colorectal cancer but for the vast majority of dietary factors the evidence was either inconclusive or limited. Most of the evidence regarding diet and risk of cancer occurrence emerges from observational studies. The aim of this study is to overcome their inherent limitations using the Mendelian randomization (MR) approach. Associations were estimated between genetically determined intakes of dietary factors and risk of colorectal cancer. We run analyses for the following dietary factors: cereals, fresh fruits, processed meat, poultry, oily fish, non-oily fish, cheese, tea and green tea. Methods: A two-sample MR study was conducted using summary data. Data for the association between the selected SNPs and risk of colorectal cancer were retrieved from 58,221 cases and 67,694 controls from GECCO. Diet factors were selected from World Cancer Research Fund (WCRF) Continuous Update Project (CUP) and summary data of their association with the SNPs stemmed from GWAS from the UK Biobank. Inverse Variance Weighted (IVW) method was implemented for the assessment of potential causality and sensitivity analyses (simple median, weighted median, MR-Egger weighted mode, MR-PRESSO) were performed to secure the non-violation of the MR assumptions. Subgroup analyses were conducted according to cancer anatomical distribution (colon, distal colon, proximal colon and rectal cancer). Results: One standard deviation (SD: highest vs lowest consumption) higher genetically determined consumption of oily fish was associated with a 27% (Odds Ratio [OR]= 0.73, 95% Confidence Interval [CI]=(0.58 -0.92), 30% (OR=0.70, 95% CI=0.54 -0.91)) and 37% (OR= 0.63, 95% CI=(0.46 -0.85)) lower risk of colorectal, colon and distal colon cancer, respectively. An inverse association was observed for a SD higher genetically determined consumption of cereals and rectal cancer (OR=0.59, 95% CI=(0.38-0.89)). A suggestive inverse association was observed for a SD higher genetically determined consumption of cereals with overall colorectal cancer (OR= 0.75, 95% CI=(0.55-1.01)). A suggestive inverse association was observed for a SD higher genetically determined consumption of fresh fruits with distal cancer (OR= 0.58, 95% CI=(0.37-0.89)) but was not robust to sensitivity analyses. There was no evidence that any of the other dietary factors were associated with colorectal cancer. Conclusions: There was an inverse association between oily fish and colorectal cancer, colon cancer and distal colon cancer. A suggestive inverse association was observed between cereals and both colorectal and rectal cancer. However, strong evidence cannot be proven due to potential pleiotropy. Further work is required to replicate and strengthen these findings

Appraising the causal role of risk factors in coronary artery disease and stroke:A systematic review of Mendelian Randomization studies

BACKGROUND Mendelian randomization (MR) offers a powerful approach to study potential causal associations between exposures and health outcomes by using genetic variants associated with an exposure as instrumental variables. In this systematic review, we aimed to summarize previous MR studies and to evaluate the evidence for causality for a broad range of exposures in relation to coronary artery disease and stroke. METHODS AND RESULTS MR studies investigating the association of any genetically predicted exposure with coronary artery disease or stroke were identified. Studies were classified into 4 categories built on the significance of the main MR analysis results and its concordance with sensitivity analyses, namely, robust, probable, suggestive, and insufficient. Studies reporting associations that did not perform any sensitivity analysis were classified as nonevaluable. We identified 2725 associations eligible for evaluation, examining 535 distinct exposures. Of them, 141 were classified as robust, 353 as probable, 110 as suggestive, and 926 had insufficient evidence. The most robust associations were observed for anthropometric traits, lipids, and lipoproteins and type 2 diabetes with coronary artery; disease and clinical measurements with coronary artery disease and stroke; and thrombotic factors with stroke. CONCLUSIONS Despite the large number of studies that have been conducted, only a limited number of associations were supported by robust evidence. Approximately half of the studies reporting associations presented an MR sensitivity analysis along with the main analysis that further supported the causality of associations. Future research should focus on more thorough assessments of sensitivity MR analyses and further assessments of mediation effects or nonlinearity of associations

Links between the genetic determinants of morning plasma cortisol and body shape: a two-sample Mendelian randomisation study

Abstract High cortisol production in Cushing’s syndrome leads to fat centralisation. The influence of modest cortisol variations on body shape, however, is less clear. We examined potentially causal associations between morning plasma cortisol and body shape and obesity with inverse-variance weighted random-effects models in a two-sample Mendelian randomisation analysis. We used publicly available summary statistics from the CORtisol NETwork (CORNET) consortium, UK Biobank, and the Genetic Investigation of Anthropometric Traits (GIANT) consortium. Only in women, morning plasma cortisol (proxied by ten genetic polymorphisms) was associated positively with waist size reflected in waist-to-hip index (WHI, 0.035 standard deviation (SD) units change per one SD cortisol increase; 95% confidence interval (0.002–0.067); p = 0.036) and “a body shape index” (ABSI; 0.039 (0.006–0.071); p = 0.021). There was no evidence for associations with hip index (HI) or body mass index (BMI). Among individual polymorphisms, rs7450600 stood out (chromosome 6; Long Intergenic Non-Protein-Coding RNA 473 gene, LINC00473). Morning plasma cortisol proxied by rs7450600 was associated positively with WHI and inversely with HI and BMI in women and men. Our findings support a causal association of higher morning plasma cortisol with larger waist size in women and highlight LINC00473 as a genetic link between morning plasma cortisol and body shape

Individualized Approach in the Surgical Management of Hepatocellular Carcinoma: Results from a Greek Multicentre Study

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of death worldwide. The management of HCC is complex, with surgical treatment providing long-term survival in eligible patients. This study aims to present the experience of aggressive surgical management of HCC in Greece. Methods: This is a retrospective multicentre clinical study with 242 patients. Results: Most patients were male (79%) and had a median age of 71 yrs. According to the most recent BCLC criteria, 172 patients (71.1%) were classified as BCLC 0-A stage, 33 patients (13.6%) were classified as BCLC B, and 37 (15.3%) were classified as BCLC C. A total of 54% of the patients underwent major hepatectomy. Major postoperative morbidity was 15.6%, and the 90-day postoperative mortality rate was 4.5%. The median follow-up was 33.5 months. Three- and five-year overall survival was 65% and 48%, respectively. The median overall survival was 55 months. Significantly, five-year survival was 55% for BCLC A, and 34% and 21% for BCLC B and C, respectively. In univariate analysis, cirrhosis, type of resection (R status), and BCLC stage were associated with overall survival. Multivariate analysis indicated that R1 and R2 resections compared to R0, and BCLC C compared to BCLC 0-A, were independently associated with increased mortality. Conclusions: Aggressive surgical treatment of HCC offers satisfactory long-term survival prospects. A significant percentage (29%) of HCCs that underwent liver resection were of the intermediate and advanced BCLC stage. The management of patients with HCC should be discussed in multidisciplinary tumour board meetings on a case-by-case basis to be more effective

Trace metal blood concentrations in Scopoli's shearwaters (Calonectris diomedea) during 2007–2014: a systematic analysis of the largest species colony in Greece

In this study, the concentrations of cadmium (Cd), lead (Pb), chromium (Cr), copper (Cu), cobalt (Co), nickel (Ni), manganese (Mn) and zinc (Zn) were investigated in the blood of Scopoli's shearwaters (Calonectris diomedea). Blood samples (N=238) were collected from both juvenile and adult individuals during seven breeding seasons between 2007 and 2014, excluding 2013. Sampling was performed in the pristine environment of the Strofades island complex, Greece, where the largest colony of Scopoli's shearwaters is located in the Eastern Mediterranean basin. The median concentrations of the toxic metals, Cd and Pb, were 0.010 and 0.24μg/g (dry weight; dw), respectively, which were in good agreement with previous studies. The median concentrations of Co, Cr, Cu, Mn, Ni, Zn were 0.18, 1.11, 3.41, 0.29, 0.61, and 22.9μg/g dw, respectively. Inter-annual differences were observed among the concentrations of all assessed metals, except for Ni and Cd, which demonstrated similarities among female individuals. Age-group related differences were observed in both genders for Cd, Cu and Cr, but only among males for Zn. To the best of our knowledge, this is the longest multi-year biomonitoring study of select trace metals that has been conducted thus far on blood samples from Scopoli's shearwater species.info:eu-repo/semantics/publishedVersio

Appraising the Causal Role of Risk Factors in Coronary Artery Disease and Stroke: A Systematic Review of Mendelian Randomization Studies.

BACKGROUND Mendelian randomization (MR) offers a powerful approach to study potential causal associations between exposures and health outcomes by using genetic variants associated with an exposure as instrumental variables. In this systematic review, we aimed to summarize previous MR studies and to evaluate the evidence for causality for a broad range of exposures in relation to coronary artery disease and stroke. METHODS AND RESULTS MR studies investigating the association of any genetically predicted exposure with coronary artery disease or stroke were identified. Studies were classified into 4 categories built on the significance of the main MR analysis results and its concordance with sensitivity analyses, namely, robust, probable, suggestive, and insufficient. Studies reporting associations that did not perform any sensitivity analysis were classified as nonevaluable. We identified 2725 associations eligible for evaluation, examining 535 distinct exposures. Of them, 141 were classified as robust, 353 as probable, 110 as suggestive, and 926 had insufficient evidence. The most robust associations were observed for anthropometric traits, lipids, and lipoproteins and type 2 diabetes with coronary artery; disease and clinical measurements with coronary artery disease and stroke; and thrombotic factors with stroke. CONCLUSIONS Despite the large number of studies that have been conducted, only a limited number of associations were supported by robust evidence. Approximately half of the studies reporting associations presented an MR sensitivity analysis along with the main analysis that further supported the causality of associations. Future research should focus on more thorough assessments of sensitivity MR analyses and further assessments of mediation effects or nonlinearity of associations