Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline ...variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship.
For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN–B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10−4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival.
Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio HR 1.44, 95% Confidence Intervals CI: 1.21–1.71, P = 5.0 × 10−5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13–1.34, P = 1.9 × 10−6). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42–0.87, P = 6.6 × 10−3). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses.
The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.
•Analysed 83 colorectal cancer (CRC)-risk loci in 1948 patients with advanced CRC for prognostic outcome.•CDH1 variants were highly associated with overall survival in multivariate analysis.•Patients with rs12597188 minor alleles had a decrease in life expectancy of 5 months.•rs12597188 was also associated with poor response to therapy.•CDH1 (E-cadherin) involved in epithelial to mesenchymal transition during metastasis.
Environmental chemical contamination is a recognised risk factor for psychological distress, but has been seldom studied in the context of per- and polyfluoroalkyl substances (PFAS) contamination. We ...examined psychological distress in a cross-sectional study of three Australian communities exposed to PFAS from the historical use of aqueous film-forming foam in firefighting activities, and three comparison communities without environmental contamination.
Participation was voluntary following recruitment from a PFAS blood-testing program (exposed) or random selection (comparison). Participants provided blood samples and completed a survey on their exposure history, sociodemographic characteristics, and four measures of psychological distress (Kessler-6, Distress Questionnaire-5, Patient Health Questionnaire-15, and Generalised Anxiety Disorder-7). We estimated prevalence ratios (PR) of clinically-significant psychological distress scores, and differences in mean scores: (1) between exposed and comparison communities; (2) per doubling in PFAS serum concentrations in exposed communities; (3) for factors that affect the perceived risk of living in a community exposed to PFAS; and (4) in relation to self-reported health concerns.
We recruited 881 adults in exposed communities and 801 in comparison communities. We observed higher levels of self-reported psychological distress in exposed communities than in comparison communities (e.g., Katherine compared to Alice Springs, Northern Territory: clinically-significant anxiety scores, adjusted PR = 2.82, 95 % CI 1.16–6.89). We found little evidence to suggest that psychological distress was associated with PFAS serum concentrations (e.g., Katherine, PFOS and anxiety, adjusted PR = 0.85, 95 % CI 0.65–1.10). Psychological distress was higher among exposed participants who were occupationally exposed to firefighting foam, used bore water on their properties, or were concerned about their health.
Psychological distress was substantially more prevalent in exposed communities than in comparison communities. Our findings suggest that the perception of risks to health, rather than PFAS exposure, contribute to psychological distress in communities with PFAS contamination.
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•Living in an area contaminated by environmental toxicants may lead to psychological distress.•We examined PFAS exposure and psychological distress (K6, DQ5, PHQ-15, GAD-7).•Psychological distress was more prevalent in exposed than comparison communities.•PFAS concentrations in blood serum were not associated with psychological distress.•Occupational use of firefighting foams was associated with psychological distress.
We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated ...through changes in body fat.
Common genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. To control for confounding effects of obesity, we included instrumental variables for body mass index (BMI), body fat percentage, waist circumference and arm, trunk and leg fat ratios. We analysed the effect of these instrumental variables in a colorectal cancer genome-wide association study comprising 31,197 cases and 61,770 controls of European ancestry by applying two-sample and multivariable MR study designs.
We found decreased colorectal cancer risk for genetically represented measures of MVPA and AMPA that were additional to effects mediated through genetic measures of obesity. Odds ratio and 95% confidence interval (CI) per standard deviation increase in MVPA and AMPA was 0.56 (0.31, 1.01) and 0.60 (0.41, 0.88), respectively. No association has been found between sedentary time and colorectal cancer risk. The proportion of effect mediated through BMI was 2% (95% CI: 0, 14) and 32% (95% CI: 12, 46) for MVPA and AMPA, respectively.
These findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness.
Associations between colorectal cancer (CRC) and other health outcomes have been reported, but these may be subject to biases, or due to limitations of observational studies.
We set out to determine ...whether genetic predisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and tree-structured phenotypic model (TreeWAS), we studied 334,385 unrelated White British individuals (excluding CRC patients) from the UK Biobank cohort. We generated a polygenic risk score (PRS) from CRC genome-wide association studies as a measure of CRC risk. We performed sensitivity analyses to test the robustness of the results and searched the Danish Disease Trajectory Browser (DTB) to replicate the observed associations.
Eight PheWAS phenotypes and 21 TreeWAS nodes were associated with CRC genetic predisposition by PheWAS and TreeWAS, respectively. The PheWAS detected associations were from neoplasms and digestive system disease group (e.g. benign neoplasm of colon, anal and rectal polyp and diverticular disease). The results from the TreeWAS corroborated the results from the PheWAS. These results were replicated in the observational data within the DTB.
We show that benign colorectal neoplasms share genetic aetiology with CRC using PheWAS and TreeWAS methods. Additionally, CRC genetic predisposition is associated with diverticular disease.
The novel coronavirus disease 2019 (COVID-19) pandemic brought about several features that increased the sense of fear and confusion, such as quarantine and financial losses among other stressors, ...which may have led to adverse psychosocial outcomes. The influence of such stressors took place within a broader sociocultural context that needs to be considered. The objective was to examine how the psychological response to the pandemic varied across countries and identify which risk/protective factors contributed to this response. An online survey was conducted from 29 May 2020-12 June 2020, among a multinational sample of 8806 adults from eight countries/regions (Canada, United States, England, Switzerland, Belgium, Hong Kong, Philippines, New Zealand). Probable generalized anxiety disorder (GAD) and major depression episode (MDE) were assessed. The independent role of a wide range of potential factors was examined using multilevel logistic regression. Probable GAD and MDE were indicated by 21.0% and 25.5% of the respondents, respectively, with an important variation according to countries/regions (GAD: 12.2-31.0%; MDE: 16.7-32.9%). When considered together, 30.2% of the participants indicated probable GAD or MDE. Several factors were positively associated with a probable GAD or MDE, including (in descending order of importance) weak sense of coherence (SOC), lower age, false beliefs, isolation, threat perceived for oneself/family, mistrust in authorities, stigma, threat perceived for country/world, financial losses, being a female, and having a high level of information about COVID-19. Having a weak SOC yielded the highest adjusted odds ratio for probable GAD or MDE (3.21; 95% confidence interval (CI): 2.73-3.77). This pandemic is having an impact on psychological health. In some places and under certain circumstances, however, people seem to be better protected psychologically. This is a unique opportunity to evaluate the psychosocial impacts across various sociocultural backgrounds, providing important lessons that could inform all phases of disaster risk management.
Epidemiological studies have linked lifestyle, cardiometabolic, reproductive, developmental, and inflammatory factors to the risk of colorectal cancer. However, which specific factors affect risk and ...the strength of these effects are unknown. We aimed to examine the relationship between potentially modifiable risk factors and colorectal cancer.
We used a random-effects model to examine the relationship between 39 potentially modifiable risk factors and colorectal cancer in 26 397 patients with colorectal cancer and 41 481 controls (ie, people without colorectal cancer). These population data came from a genome-wide association study of people of European ancestry, which was amended to exclude UK BioBank data. In the model, we used genetic variants as instruments via two-sample mendelian randomisation to limit bias from confounding and reverse causation. We calculated odds ratios per genetically predicted SD unit increase in each putative risk factor (ORSD) for colorectal cancer risk. We did mendelian randomisation Egger regressions to identify evidence of potential violations of mendelian randomisation assumptions. A Bonferroni-corrected threshold of p=1·3 × 10−3 was considered significant, and p values less than 0·05 were considered to be suggestive of an association.
No putative risk factors were significantly associated with colorectal cancer risk after correction for multiple testing. However, suggestive associations with increased risk were noted for genetically predicted body fat percentage (ORSD 1·14 95% CI 1·03–1·25; p=0·0086), body-mass index (1·09 1·01–1·17; p=0·023), waist circumference (1·13 1·02–1·26; p=0·018), basal metabolic rate (1·10 1·03–1·18; p=0·0079), and concentrations of LDL cholesterol (1·14 1·04–1·25; p=0·0056), total cholesterol (1·09 1·01–1·18; p=0·025), circulating serum iron (1·17 1·00–1·36; p=0·049), and serum vitamin B12 (1·21 1·04–1·42; p=0·016), although potential pleiotropy among genetic variants used as instruments for vitamin B12 constrains the finding. A suggestive association was also noted between adult height and increased risk of colorectal cancer (ORSD 1·04 95% CI 1·00–1·08; p=0·032). Low blood selenium concentration had a suggestive association with decreased risk of colorectal cancer (ORSD 0·85 95% CI 0·75–0·96; p=0·0078) based on a single variant, as did plasma concentrations of interleukin-6 receptor subunit α (also based on a single variant; 0·98 0·96–1·00; p=0·035). Risk of colorectal cancer was not associated with any sex hormone or reproductive factor, serum calcium, or circulating 25-hydroxyvitamin D concentrations.
This analysis identified several modifiable targets for primary prevention of colorectal cancer, including lifestyle, obesity, and cardiometabolic factors, that should inform public health policy.
Cancer Research UK, UK Medical Research Council Human Genetics Unit Centre, DJ Fielding Medical Research Trust, EU COST Action, and the US National Cancer Institute.
Abstract
Background
The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian randomization (MR) framework to examine if lifestyle, cardiometabolic, and ...inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation.
Methods
We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12 488 glioma patients and 18 169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures:
Lifestyle and dietary factors—height, plasma insulin-like growth factor 1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamins (A1, B12, B6, E, and 25-hydroxyvitamin D), fatty acid levels (monounsaturated, omega-3, and omega-6) and circulating fetuin-A;
Cardiometabolic factors—birth weight, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, glycated hemoglobin levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio; and
Inflammatory factors— C-reactive protein, plasma interleukin-6 receptor subunit alpha and serum immunoglobulin E.
Results
After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism, no significant association with glioma risk was observed (ie, PCorrected > 0.05).
Conclusions
This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk.
The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search ...for glioma risk factors.
We performed an MR-PheWAS analysing 316 phenotypes, proxied by 8387 genetic variants, and summary genetic data from a GWAS of 12,488 glioma cases and 18,169 controls. Causal effects were estimated under a random-effects inverse-variance-weighted (IVW-RE) model, with robust adjusted profile score (MR-RAPS), weighted median and mode-based estimates computed to assess the robustness of findings. Odds ratios per one standard deviation increase in each phenotype were calculated for all glioma, glioblastoma (GBM) and non-GBM tumours.
No significant associations (P < 1.58 × 10
) were observed between phenotypes and glioma under the IVW-RE model. Suggestive associations (1.58 × 10
< P < 0.05) were observed between leukocyte telomere length (LTL) with all glioma (OR
= 3.91, P = 9.24 × 10
) and GBM (OR
= 4.86, P = 3.23 × 10
), but the association was primarily driven by the TERT variant rs2736100. Serum low-density lipoprotein cholesterol and plasma HbA1C showed suggestive associations with glioma (OR
= 1.11, P = 1.39 × 10
and OR
= 1.28, P = 1.73 × 10
, respectively), both associations being reliant on single genetic variants.
Our study provides further insight into the aetiological basis of glioma for which published data have been mixed.
Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible ...confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR).
We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (OR
) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions.
No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (OR
= 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown.
Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.
The COVID-19 pandemic and countries' response measures have had a globally significant mental health impact. This mental health burden has also been fueled by an infodemic: an information overload ...that includes misinformation and disinformation. Suicide, the worst mental health outcome, is a serious public health problem that can be prevented with timely, evidence-based, and often low-cost interventions. Suicide ideation, one important risk factor for suicide, is thus important to measure and monitor, as are the factors that may impact on it.
This investigation had 2 primary aims: (1) to estimate and compare country-specific prevalence of suicide ideation at 2 different time points, overall and by gender and age groups, and (2) to investigate the influence of sociodemographic and infodemic variables on suicide ideation.
A repeated, online, 8-country (Canada, the United States, England, Switzerland, Belgium, Hong Kong, Philippines, and New Zealand), cross-sectional study was undertaken with adults aged ≥18 years, with measurement wave 1 conducted from May 29, 2020 to June 12, 2020 and measurement wave 2 conducted November 6-18, 2021. Self-reported suicide ideation was derived from item 9 of the Patient Health Questionnaire-9 (PHQ-9). Age-standardized suicide ideation rates were reported, a binomial regression model was used to estimate suicide ideation indication rates for each country and measurement wave, and logistic regression models were then employed to relate sociodemographic, pandemic, and infodemic variables to suicide ideation.
The final sample totaled 17,833 adults: 8806 (49.4%) from measurement wave 1 and 9027 (50.6%) from wave 2. Overall, 24.2% (2131/8806) and 27.5% (2486/9027) of participants reported suicide ideation at measurement waves 1 and 2, respectively, a difference that was significant (P<.001). Considerable variability was observed in suicide ideation age-standardized rates between countries, ranging from 15.6% in Belgium (wave 1) to 42.9% in Hong Kong (wave 2). Frequent social media usage was associated with increased suicide ideation at wave 2 (adjusted odds ratio AOR 1.47, 95% CI 1.25-1.72; P<.001) but not wave 1 (AOR 1.11, 95% CI 0.96-1.23; P=.16). However, having a weaker sense of coherence (SOC; AOR 3.80, 95% CI 3.18-4.55 at wave 1 and AOR 4.39, 95% CI 3.66-5.27 at wave 2; both P<.001) had the largest overall effect size.
Suicide ideation is prevalent and significantly increasing over time in this COVID-19 pandemic era, with considerable variability between countries. Younger adults and those residing in Hong Kong carried disproportionately higher rates. Social media appears to have an increasingly detrimental association with suicide ideation, although having a stronger SOC had a larger protective effect. Policies and promotion of SOC, together with disseminating health information that explicitly tackles the infodemic's misinformation and disinformation, may importantly reduce the rising mental health morbidity and mortality triggered by this pandemic.
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