Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis

Abstract Background 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). Methods 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 (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. Results No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96–1.03, P value = 0.90) with CRC was shown. Conclusions 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.

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Colorectal Cancer Prevalence and Survival in Castilla La Mancha (Spain). A Pilot Study

10.21203/rs.3.rs-926142/v1 ◽

2021 ◽

Author(s):

Laura Valiente González ◽

Ricardo de Miguel Ibáñez ◽

Francisco Escribano Sotos

Keyword(s):

Colorectal Cancer ◽

Pilot Study ◽

Large Scale ◽

Cox Regression ◽

Epidemiological Studies ◽

Cancer Type ◽

Tumour Stage ◽

Cancer Prevalence ◽

La Mancha

Abstract Background: Colorectal cancer is the most commonly diagnosed cancer type and the second cause of cancer death in Spain. The primary risk factor for colorectal cancer is age, with 90% of all diagnosed patients aged over 50 years. Prognosis mainly depends on tumour stage. Aim: Conduct a pilot Colorectal Cancer prevalence and survival study in Cuenca (Spain) since there are almost no studies based on small populations. This is the first pilot study about survival in screening of colorectal cancer carried out in hospitals in Castilla La Mancha. Methods and Results: Retrospective descriptive cohort study was performed to include patients with colorectal cancer diagnosed by colonoscopy between May 2015 and April 2016, and who were followed up for 48 months. The study considered sociodemographic and clinical data of the patients. Survival curves were estimated using the Kaplan-Meier method. The proportional hazard rate associated with age, gender, stage and presence of metastasis was calculated using the Cox regression method. 57 patients were included in the study. The mean follow-up was 45.5 months. Ten patients died during the study, in seven cases the cause was colorectal cancer. The percentage of patients alive at 48-month follow-up were 82.4%. Conclusion: Colon cancer is a high-prevalence pathology, with adenocarcinoma being the most common histology. The results seem to indicate that it affects men more frequently, mortality rises with tumour stage at diagnosis and declines with use of chemotherapy. We present a pilot study that could justify large-scale epidemiological studies for the regional surveillance and evolution of colorectal cancer in Spain.

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Polynomial Mendelian Randomization reveals widespread non-linear causal effects in the UK Biobank

10.1101/2021.12.08.471751 ◽

2021 ◽

Author(s):

Jonathan Sulc ◽

Jenny Sjaarda ◽

Zoltan Kutalik

Keyword(s):

Causal Inference ◽

Large Scale ◽

Causal Effect ◽

Causal Effects ◽

Mendelian Randomisation ◽

Uk Biobank ◽

Individual Level ◽

Glucose Levels ◽

Causal Function ◽

The Uk

Causal inference is a critical step in improving our understanding of biological processes and Mendelian randomisation (MR) has emerged as one of the foremost methods to efficiently interrogate diverse hypotheses using large-scale, observational data from biobanks. Although many extensions have been developed to address the three core assumptions of MR-based causal inference (relevance, exclusion restriction, and exchangeability), most approaches implicitly assume that any putative causal effect is linear. Here we propose PolyMR, an MR-based method which provides a polynomial approximation of an (arbitrary) causal function between an exposure and an outcome. We show that this method provides accurate inference of the shape and magnitude of causal functions with greater accuracy than existing methods. We applied this method to data from the UK Biobank, testing for effects between anthropometric traits and continuous health-related phenotypes and found most of these (84%) to have causal effects which deviate significantly from linear. These deviations ranged from slight attenuation at the extremes of the exposure distribution, to large changes in the magnitude of the effect across the range of the exposure (e.g. a 1 kg/m2 change in BMI having stronger effects on glucose levels if the initial BMI was higher), to non-monotonic causal relationships (e.g. the effects of BMI on cholesterol forming an inverted U shape). Finally, we show that the linearity assumption of the causal effect may lead to the misinterpretation of health risks at the individual level or heterogeneous effect estimates when using cohorts with differing average exposure levels.

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Systemic evaluation of the relationship between psoriasis, psoriatic arthritis and osteoporosis: observational and Mendelian randomisation study

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-217892 ◽

2020 ◽

Vol 79 (11) ◽

pp. 1460-1467 ◽

Cited By ~ 3

Author(s):

Jiangwei Xia ◽

Shu-Yang Xie ◽

Ke-Qi Liu ◽

Lin Xu ◽

Pian-Pian Zhao ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Causal Effect ◽

Genetic Risk Score ◽

Final Analysis ◽

Ultrasound Measurement ◽

Mendelian Randomisation ◽

Mineral Density ◽

Medication Treatment ◽

Weighted Genetic Risk Score ◽

The Relationship

Objectives and methodsWith 432 513 samples from UK Biobank dataset, multivariable linear/logistic regression were used to estimate the relationship between psoriasis/psoriatic arthritis (PsA) and estimated bone mineral density (eBMD)/osteoporosis, controlling for potential confounders. Here, confounders were set in three ways: model0 (including age, height, weight, smoking and drinking), model1 (model0 +regular physical activity) and model2 (model1 +medication treatments). The eBMD was derived from heel ultrasound measurement. And 4904 patients with psoriasis and 847 patients with PsA were included in final analysis. Mendelian randomisation (MR) approach was used to evaluate the causal effect between them.ResultsLower eBMD were observed in patients with PsA than in controls in both model0 (β-coefficient=−0.014, p=0.0006) and model1 (β-coefficient=−0.013, p=0.002); however, the association disappeared when conditioning on treatment with methotrexate or ciclosporin (model2) (β-coefficient=−0.005, p=0.28), mediation analysis showed that 63% of the intermediary effect on eBMD was mediated by medication treatment (p<2E-16). Patients with psoriasis without arthritis showed no difference of eBMD compared with controls. Similarly, the significance of higher risk of osteopenia in patients with PsA (OR=1.27, p=0.002 in model0) could be eliminated by conditioning on medication treatment (p=0.244 in model2). Psoriasis without arthritis was not related to osteopenia and osteoporosis. The weighted Genetic Risk Score analysis found that genetically determined psoriasis/PsA were not associated with eBMD (p=0.24 and p=0.88). Finally, MR analysis showed that psoriasis/PsA had no causal effect on eBMD, osteoporosis and fracture.ConclusionsThe effect of PsA on osteoporosis was secondary (eg, medication) but not causal. Under this hypothesis, psoriasis without arthritis was not a risk factor for osteoporosis.

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A trial sequential meta-analysis of TNF-α –308G>A (rs800629) gene polymorphism and susceptibility to colorectal cancer

Bioscience Reports ◽

10.1042/bsr20181052 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 1

Author(s):

Raju K. Mandal ◽

Munawwar Ali Khan ◽

Arif Hussain ◽

Naseem Akhter ◽

Arshad Jawed ◽

...

Keyword(s):

Colorectal Cancer ◽

Gene Polymorphism ◽

Meta Analysis ◽

Asian Population ◽

Epidemiological Studies ◽

Pooled Analysis ◽

Asian Ethnicity ◽

Tnf Α ◽

Factor Α ◽

The Relationship

Abstract Purpose: Tumor necrosis factor-α (TNF-α), secreted by the activated macrophages, may participate in the onset and progression of colorectal cancer (CRC). The association of TNF-α –308 G>A (rs1800629) single-nucleotide polymorphism (SNP) with CRC risk has been investigated by many studies but the results are inconclusive. A trial sequential meta-analysis was performed for precise estimation of the relationship between TNF-α –308 G>A gene polymorphism with CRC risk. Methods: Medline (PubMed), EMBASE (Excerpta-Medica) and Google Scholar were mined for relevant articles. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the significance of association. Results: The pooled analysis indicated no risk associated with TNF-α –308 G>A SNP and overall CRC risk in five genetic comparison models, i.e. allelic (A vs. G: P = 0.524; OR = 1.074, 95% CI = 0.863–1.335), homozygous (AA vs. GG: P = 0.489; OR = 1.227, 95% CI = 0.688–2.188), heterozygous (AG vs. GG: P = 0.811; OR = 1.024, 95% CI = 0.843–1.244), dominant (AA+AG vs. GG: P = 0.630; OR = 1.055, 95% CI = 0.849–1.311) and recessive (AA vs. AG+GG: P = 0.549; OR = 1.181, 95% CI = 0.686–2.033). Subgroup analysis revealed that TNF-α –308 G>A SNP is associated with reduced risk of CRC in Asian ethnicity. The study showed no publication bias. Conclusions: No association of TNF-α –308 G>A SNP with overall CRC risk was found. This SNP is likely to be protective against CRC in Asian population when compared with Caucasian population. Larger prospective-epidemiological studies are warranted to elucidate the roles of TNF-α –308 G>A SNP in the etiology of CRC and to endorse the present findings.

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Evaluating the relationship between SIF and GPP under climate extremes

10.5194/egusphere-egu21-8939 ◽

2021 ◽

Author(s):

Sebastian Wieneke ◽

Ana Bastos ◽

Manuela Balzarolo ◽

José Miguel Barrios ◽

Ivan Janssens

Keyword(s):

Large Scale ◽

Gross Primary Production ◽

Vegetation Indices ◽

Climate Extremes ◽

Vegetation Stress ◽

Linear Relationships ◽

Forest Sites ◽

Good Proxy ◽

The Relationship

Sun Induced Chlorophyll Fluorescence (SIF) is considered as a good proxy for photosynthesis given its closer link to the photosynthetic light reactions compared to remote sensing vegetation indices typically used for ecosystem productivity modelling (eg. NDVI). Satellite-based SIF shows significant linear relationships with gross primary production (GPP) from in-situ measurements across sites, biomes and seasons. While SIF can be considered a good proxy for large scale spatial and seasonal variability in GPP, much of the SIF-GPP co-variance can be explained by their common dependence on the absorbed photosynthetically active radiation. Whether SIF can be an equally good proxy for interannual variability in GPP especially during periods of vegetation stress (drought/heat) is, so far, not clear.In this study, we evaluate the relationship between satellite-based SIF and in-situ GPP measurements during vegetation stress periods (drought/heat), compared to non-stress periods. GPP is obtained from eddy-covariance measurements from a set of forest sites pre-filtered to ensure homonegeous footprints. SIF is obtained from GOME-2 covering the period 2007-2018. Because of scale mismatch between each site&#8217;s footprint (in the order of hundred meters) and the spatial resolution of GOME-2 (ca. 50km), we additionally use SIF from the downscale product from Duveiller et al. 2020 (ca. 5km) and the more recent dataset from TROPOMI (ca. 7 x 3.5 km), covering only the last year of the study period.We develop a classification of stress periods that is based on both the occurrence of drought/heat extreme events and the presence of photosynthetic downregulation. We then evaluate the relationship between SIF and GPP and their yields, for different plant functional types and at site-level. We evaluate how these relationships vary depending on environmental conditions and in particular for &#8220;stress&#8221; versus &#8220;non-stress&#8221; days.Duveiller, G., Filipponi, F., Walther, S., K&#246;hler, P., Frankenberg, C., Guanter, L., and Cescatti, A.: A spatially downscaled sun-induced fluorescence global product for enhanced monitoring of vegetation productivity, Earth Syst. Sci. Data, 12, 1101&#8211;1116, https://doi.org/10.5194/essd-12-1101-2020, 2020.

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Evidence based legislation? Adequate protection of EU citizens against aircraft noise – Discussion of current scientific knowledge on aircraft noise with respect to EU legislation concerning noise protection

elni Review ◽

10.46850/elni.2016.004 ◽

2016 ◽

pp. 26-32

Author(s):

Franziska Heß ◽

Martin Führ

Keyword(s):

Large Scale ◽

Noise Exposure ◽

Epidemiological Studies ◽

Learning Disorders ◽

Aircraft Noise ◽

Myocardial Infarctions ◽

Limit Values ◽

Legal Implications ◽

The Relationship ◽

Health Impairments

This article focuses on air noise protection in European law. The consideration of legal implications is based on a meta study (synopsis) of scientific research on aircraft noise-induced health impairments, annoyance and learning disorders. The synopsis concludes that the association of noise with an increased incidence of chronic arterial hypertension has been shown in large-scale epidemiological studies and reproduced with sophisticated methodology. It is therefore considered scientifically confirmed. In addition to hypertension, the relationship between aircraft noise and the risk of myocardial infarctions as well as strokes has been discussed. Based on recent epidemiological studies the relationship can also be considered scientifically confirmed. However, with regard to heart failure an association is very likely, but not enough studies are available to allow a definite statement. By reviewing the current studies, the authors held that legally standardized immission limit values for aircraft noise exposure must be provided in order to protect residents in the vicinity of airports. From the available studies an upper limit of 50 dB(A) for Lden as a 24 h value and 45 dB(A) for Lnight are to be derived to avoid annoyance, cognitive constrictions and health impairments. To avoid sleeping disorder at night, an 8 hour period without noise is required.

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The Relationship between Cholecystectomy, Unoperated Gallstone Disease, and Colorectal Cancer: A Necropsy Study

Scandinavian Journal of Gastroenterology ◽

10.3109/00365529509096347 ◽

1995 ◽

Vol 30 (10) ◽

pp. 1017-1020 ◽

Cited By ~ 9

Author(s):

P. M. Mercer ◽

F. D. A. Reid ◽

M. Harrison ◽

T. Bates

Keyword(s):

Colorectal Cancer ◽

Gallstone Disease ◽

The Relationship

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Smoking and COVID-19 outcomes: an observational and Mendelian randomisation study using the UK Biobank cohort

Thorax ◽

10.1136/thoraxjnl-2021-217080 ◽

2021 ◽

pp. thoraxjnl-2021-217080

Author(s):

Ashley K Clift ◽

Adam von Ende ◽

Pui San Tan ◽

Hannah M Sallis ◽

Nicola Lindson ◽

...

Keyword(s):

Large Scale ◽

Hospital Admissions ◽

Causal Effect ◽

Smoking Status ◽

Smoking Initiation ◽

Mendelian Randomisation ◽

Uk Biobank ◽

Never Smokers ◽

The Uk ◽

Analytical Approaches

BackgroundConflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity.MethodsWe undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase).ResultsThere were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1–9/day: OR 2.14, 95% CI 0.87 to 5.24; 10–19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72).InterpretationCongruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.

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Genetic correlation and causal relationships between cardio-metabolic traits and Lung function Impairment

10.1101/2020.09.16.20190306 ◽

2020 ◽

Author(s):

Matthias Wielscher ◽

Andre FS Amaral ◽

Diana van der Plaat ◽

Louise V Wain ◽

Sylvain Sebert ◽

...

Keyword(s):

Blood Pressure ◽

Lung Function ◽

Genetic Correlation ◽

Large Scale ◽

Causal Effect ◽

Association Studies ◽

Metabolic Health ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Metabolic Traits

Background: Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. Methods We performed three analyses: 1) cardio-metabolic health to lung function association tests in NFBC1966, 2) cross trait LD score regression to compare genetic backgrounds and 3) Mendelian Randomization (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from UK Biobank data or published large-scale genome-wide association studies (N > 82,000). Results We observed negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR) we found associations between Type 2 Diabetes instruments and FVC as well as FEV1/FVC. BMI instruments were associated to all lung function traits and CRP instruments to FVC. These genetic association provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. Conclusions: The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being mediated by CRP. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

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Mendelian randomisation with coarsened exposures

10.1101/2020.08.20.20178921 ◽

2020 ◽

Author(s):

Matthew J. Tudball ◽

Jack Bowden ◽

Rachael A. Hughes ◽

Amanda Ly ◽

Marcus R. Munafò ◽

...

Keyword(s):

Genetic Variance ◽

Epidemiological Studies ◽

Simple Expression ◽

Effect Sizes ◽

Mendelian Randomisation ◽

Exposure Measurement ◽

Continuous Trait ◽

The One ◽

The Relationship ◽

Genetic Instruments

AbstractA key assumption in Mendelian randomisation is that the relationship between the genetic instruments and the outcome is fully mediated by the exposure, known as the exclusion restriction assumption. However, in epidemiological studies, the exposure is often a coarsened approximation to some latent continuous trait. For example, latent liability to schizophrenia can be thought of as underlying the binary diagnosis measure. Genetically-driven variation in the outcome can exist within categories of the exposure measurement, thus violating this assumption. We propose a framework to clarify this violation, deriving a simple expression for the resulting bias and showing that it may inflate or deflate effect estimates but will not reverse their sign. We then characterise a set of assumptions and a straight-forward method for estimating the effect of standard deviation increases in the latent exposure. Our method relies on a sensitivity parameter which can be interpreted as the genetic variance of the latent exposure. We show that this method can be applied in both the one-sample and two-sample settings. We conclude by demonstrating our method in an applied example and re-analysing two papers which are likely to suffer from this type of bias, allowing meaningful interpretation of their effect sizes.

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