Konstantinos (Kostas) K Tsilidis

Background Sedentary behaviours have been associated with increased risks of some common cancers in epidemiological studies; however, it is unclear if these associations are causal. Methods We used univariable and multivariable two‐sample Mendelian randomisation (MR) to examine potential causal relationships between sedentary behaviours and risks of breast, colorectal and prostate cancer. Genetic variants associated with self‐reported leisure television watching and computer use were identified from a recent genome‐wide association study (GWAS). Data related to cancer risk were obtained from cancer GWAS consortia. A series of sensitivity analyses were applied to examine the robustness of the results to the presence of confounding. Results A 1‐standard deviation (SD: 1.5 h/day) increment in hours of television watching increased risk of breast cancer (OR per 1‐SD: 1.15, 95% confidence …

Post-diagnosis physical activity and sedentary behaviour and colorectal cancer prognosis: a Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis - White Rose Research Online White Rose logo White Rose Research Online Home Search Browse Contact Post-diagnosis physical activity and sedentary behaviour and colorectal cancer prognosis: a Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis Markozannes, G., Becerra-Tomás, N., Cariolou, M. et al. (27 more authors) (Accepted: 2024) Post-diagnosis physical activity and sedentary behaviour and colorectal cancer prognosis: a Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis. International Journal of Cancer. ISSN 0020-7136 (In Press) Metadata Authors/Creators: Markozannes, G. Becerra-Tomás, N. Cariolou, M. Balducci, K. …

BackgroundTumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.MethodsWe meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10−8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage …

BackgroundMenopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk.MethodsWe used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated.ResultsThe reduction in odds ratios by MHT use was larger in women …

IntroductionComprehensive characteristics of the glycemic profile for prediabetes derived by continuous glucose monitoring (CGM) are unknown. We evaluate the difference of CGM profiles between individuals with prediabetes and normoglycemic individuals, including the response to oral glucose tolerance test (OGTT).MethodsIndividuals with prediabetes matched for age, sex, and BMI with normoglycemic individuals were instructed to use professional CGM for 1 week. OGTT was performed on the second day. The primary outcomes were percentages of glucose readings time below range (TBR): <54 or <70 mg/dL, time in range (TIR): 70 to 180 mg/dL, and time above range (TAR): >180 or >250 mg/dL. Area under the curve (AUC) was calculated following the OGTT. Glucose variability was depicted by coefficient of variation (CV), SD, and mean amplitude of glucose excursion (MAGE). Wilcoxon sign-ranked test …

Background Obesity and diabetes are associated inversely with low‐grade prostate cancer risk and affect steroid hormone synthesis but whether they modify each other's impact on prostate cancer risk remains unknown. Methods We examined the independent associations of diabetes, body mass index (BMI), ‘a body shape index’ (ABSI), hip index (HI), circulating testosterone, sex hormone binding globulin (SHBG) (per one standard deviation increase) and oestradiol ≥175 pmol/L with total prostate cancer risk using multivariable Cox proportional hazards models for UK Biobank men. We evaluated multiplicative interactions (pMI) and additive interactions (relative excess risk from interaction (pRERI), attributable proportion (pAR), synergy index (pSI)) with obese (BMI ≥30 kg/m2) and diabetes. Results During a mean follow‐up of 10.3 years, 9417 incident prostate cancers were diagnosed in 195,813 men …

BackgroundTraditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing.MethodsWe used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank …

We carried out a genome-wide association and Mendelian randomization analysis to probe genetic and environmental risk factors for sarcoidosis. We performed a genome-wide meta-analysis in 5,194 sarcoidosis cases and 777,559 non-cases from the FinnGen and UK Biobank studies. We estimated the heritability, pinpointed genomic risk loci, predicted deleteriousness, mapped corresponding genes, and enriched gene expression to tissues using FUMA (Functional Mapping and Annotation) and MAGMA (Multi-marker Analysis of GenoMic Annotation) softwares. We performed Mendelian randomization analyses to investigate the links between 6 modifiable factors and 66 inflammatory markers in relation to sarcoidosis. Genetic variants associated with these exposures at the genome-wide significance level and in low linkage disequilibrium were used as instrumental variables. The heritability of sarcoidosis explained by common genetic variants was around 12%. We annotated 14 genomic loci that surpassed the genome-wide significance threshold of which 6 loci were previously unreported. The locus proximal to TYK2 had a high potential deleterious impact on protein function. MAGMA revealed notable gene expression patterns in whole blood, spleen, and lung. Genetically predicted lower levels of physical activity and higher levels of body mass index, interleukin-23 receptor, and interleukin 1 receptor-like 2 were associated with a heighted risk of sarcoidosis.

Background The link between the pre‐diagnostic use of statins and testosterone replacement therapy and their impact on hormone‐related cancers, prostate cancer, colorectal cancer, and male breast cancer survival remains a topic of controversy. Further, there is a knowledge gap concerning the joint effects of statins and testosterone replacement therapy on hormone‐related cancer survival outcomes. Objective To examine the independent and joint effects of pre‐diagnostic use of statins and testosterone replacement therapy on the risk of all‐cause and cause‐specific mortality among older men diagnosed with hormone‐related cancers, including prostate cancer, colorectal cancer, and male breast cancer. Methods In 41,707 men (≥65 years) of Surveillance, Epidemiology, and End Results‐Medicare 2007–2015, we identified 31,097 prostate cancer, 10,315 colorectal cancer, and 295 male breast cancer …

Objectives We aimed to describe the trajectories of cognitive and physical symptoms before, during, and after a positive- or negative SARS-CoV-2 test and in untested controls. Design A prospective cohort study. Setting Norway, 27 March 2020 to 6 July 2022 Participants A total of 146 065 volunteers were recruited. Of these, 120 605 participants (mean age 49 (SD 13.7), 69% female), were initially untested for the SARS-CoV-2 virus, completed one or more follow-up questionnaires (response rates 72-90%) and were included for analysis. After 22 months of follow-up, 15 737 participants had a positive SARS-CoV-2 test, 67 305 a negative test, and 37 563 were still untested. Main outcome measures We assessed reported symptoms the past three weeks of memory or concentration problems, anosmia and dysgeusia, dyspnoea, fatigue, fever, headache, cough, muscular pain, nasal symptoms, sore throat and abdominal pain at baseline and through four follow-up questionnaires. In addition, overall health compared to a year before was measured with a five-point scale and memory problems were measured using the Everyday Memory Questionnaire-13 at two timepoints. The exposure, SARS-CoV-2 test status (positive, negative or untested), was obtained from a mandatory national registry or from self-report, and data were analysed using mixed model logistic regression. Results A positive SARS-CoV-2-test was associated with the following persistent symptoms, compared with participants with a negative test (1-3 months after a negative test); memory problems (3 to 6 months after a positive test: adjusted odds ratio (OR) 9.1, 95% confidence …

Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading - White Rose Research Online White Rose logo White Rose Research Online Home Search Browse Contact Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading Tsilidis, K., Markozannes, G., Becerra-Tomás, N. et al. (36 more authors) (Accepted: 2024) Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading. International Journal of Cancer. ISSN 0020-7136 (In Press) Metadata Authors/Creators: Tsilidis, …

PurposeSleep is essential to all human body functions as well as brain functions. Inadequate sleep quantity and poor sleep quality have been shown to directly affect cognitive functioning and especially memory. The primary aim of the present study was to investigate the association of sleep quality with cognitive abilities cross-sectionally in a middle-aged Greek population and secondarily to examine this association prospectively in a smaller group of these participants.Patients and MethodsA total of 2112 healthy adults aged 25–70 years (mean: 46.7±11.5) from the Epirus Health Study cohort were included in the analysis and 312 of them participated in secondary prospective analysis. Sleep quality was measured by the Pittsburgh Sleep Quality Index (PSQI) scale and cognition was assessed in primary cross-sectional analyses with three neuropsychological tests, namely the Verbal Fluency test, the Logical …

BackgroundObesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain.MethodsWe used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO).FindingsA 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non …

BackgroundThe incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. Colorectal cancer (CRC) has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC.Patients and methodsWe conducted a genome-wide association study meta-analysis of 6,176 EOCRC cases and 65,829 controls from Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Colorectal Transdisciplinary study (CORECT), Colon Cancer Family Registry (CCFR), and UK Biobank. We then used the EOCRC GWAS to investigate …

Background Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. Methods A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. Results Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10−8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20–1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × …

Post-diagnosis adiposity and colorectal cancer prognosis: a Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis - White Rose Research Online White Rose logo White Rose Research Online Home Search Browse Contact Post-diagnosis adiposity and colorectal cancer prognosis: a Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis Becerra-Tomás, N., Markozannes, G., Cariolou, M. et al. (27 more authors) (Accepted: 2024) Post-diagnosis adiposity and colorectal cancer prognosis: a Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis. International Journal of Cancer. ISSN 0020-7136 (In Press) Metadata Authors/Creators: Becerra-Tomás, N. Markozannes, G. Cariolou, M. Balducci, K. Vieira, AR Kiss, S. Aune, D. Greenwood, DC ORCID logo https://orcid.org/0000-0001-7035-3096 …

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 …

Background High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene–environment (GxE) interaction analysis to identify genetic variants that may modify these associations. Methods A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan. Results Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval …

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 …

Adiposity is an established risk factor for colorectal cancer (CRC). However, the pathways underlying this relationship, and specifically the role of the circulating proteome, is unclear. Utilizing two-sample Mendelian randomization and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable (UV) associations between: (I) adiposity measures (body mass index, BMI; waist hip ratio, WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (II) adiposity measures and plasma proteins, and (III) adiposity-associated plasma proteins and CRC risk. We used multivariable MR (MVMR) to investigate the potential mediating role of adiposity- and CRC-related proteins in the adiposity-CRC association. BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumour site. 6,591 adiposity-protein (2,628 unique proteins) and 33 protein-CRC (8 unique proteins) associations were identified using UVMR and colocalization. 1 protein, GREM1 was associated with BMI only and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated - suggestive of a potential mediating role - most strongly for the BMI-overall CRC association in women. These results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from cis-SNP UVMR and colocalization analyses, GREM1 was …