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Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.

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; andInflammatory 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.

SUBMITTER: Saunders CN

PROVIDER: S-EPMC7442418 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.

Saunders Charlie N CN Cornish Alex J AJ Kinnersley Ben B Law Philip J PJ Claus Elizabeth B EB Il'yasova Dora D Schildkraut Joellen J Barnholtz-Sloan Jill S JS Olson Sara H SH Bernstein Jonine L JL Lai Rose K RK Chanock Stephen S Rajaraman Preetha P Johansen Christoffer C Jenkins Robert B RB Melin Beatrice S BS Wrensch Margaret R MR Sanson Marc M Bondy Melissa L ML Houlston Richard S RS

Neuro-oncology 20200201 2

<h4>Background</h4>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.<h4>Methods</h4>We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wi ...[more]

PMID: 31665421

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Project description:BackgroundPotentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR).Methods and findingsWe used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses.ConclusionsInherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.

Project description:BackgroundThe pathogenesis of pancreatitis involves diverse environmental risk factors, some of which have not yet been clearly elucidated. This study systematically investigated the causal effects of genetically predicted modifiable risk factors on pancreatitis using the Mendelian randomization (MR) approach.MethodsGenetic variants associated with 30 exposure factors were obtained from genome-wide association studies. Summary-level statistical data for acute pancreatitis (AP), chronic pancreatitis (CP), alcohol-induced AP (AAP) and alcohol-induced CP (ACP) were obtained from FinnGen consortia. Univariable and multivariable MR analyses were performed to identify causal risk factors for pancreatitis.ResultsGenetic predisposition to smoking (OR = 1.314, P = 0.021), cholelithiasis (OR = 1.365, P = 1.307E-19) and inflammatory bowel disease (IBD) (OR = 1.063, P = 0.008) as well as higher triglycerides (OR = 1.189, P = 0.016), body mass index (BMI) (OR = 1.335, P = 3.077E-04), whole body fat mass (OR = 1.291, P = 0.004) and waist circumference (OR = 1.466, P = 0.011) were associated with increased risk of AP. The effect of obesity traits on AP was attenuated after correcting for cholelithiasis. Genetically-driven smoking (OR = 1.595, P = 0.005), alcohol consumption (OR = 3.142, P = 0.020), cholelithiasis (OR = 1.180, P = 0.001), autoimmune diseases (OR = 1.123, P = 0.008), IBD (OR = 1.066, P = 0.042), type 2 diabetes (OR = 1.121, P = 0.029), and higher serum calcium (OR = 1.933, P = 0.018), triglycerides (OR = 1.222, P = 0.021) and waist-to-hip ratio (OR = 1.632, P = 0.023) increased the risk of CP. Cholelithiasis, triglycerides and the waist-to-hip ratio remained significant predictors in the multivariable MR. Genetically predicted alcohol drinking was associated with increased risk of AAP (OR = 15.045, P = 0.001) and ACP (OR = 6.042, P = 0.014). After adjustment of alcohol drinking, genetic liability to IBD had a similar significant causal effect on AAP (OR = 1.137, P = 0.049), while testosterone (OR = 0.270, P = 0.002) a triglyceride (OR = 1.610, P = 0.001) and hip circumference (OR = 0.648, P = 0.040) were significantly associated with ACP. Genetically predicted higher education and household income levels could lower the risk of pancreatitis.ConclusionsThis MR study provides evidence of complex causal associations between modifiable risk factors and pancreatitis. These findings provide new insights into potential therapeutic and prevention strategies.

Project description:BackgroundTelomere length has long been recognized as a valuable biomarker of aging and is inversely correlated with chronological age. Various lifestyle factors have been implicated in telomere shortening or preservation; however, the association between lifestyle factors and telomere length remains controversial. To address this issue, we conducted a Mendelian randomization (MR) analysis to investigate the potential causal associations between multiple lifestyle factors and telomere length.MethodsIndependent genetic variants strongly associated with lifestyle factors (tobacco smoking, sleep duration, insomnia, and physical activity) were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for telomere length was obtained from a GWAS comprising 472,174 European ancestries. Univariable and multivariable MR analyses were performed to assess the relationships.ResultsThe genetic liability to lifetime smoking was robustly associated with shorter telomere length (odd ratio [OR]: 0.882; 95% confidence interval [CI]: 0.847-0.918). Genetically predicted insomnia was also linked to shorter telomere length (OR: 0.972; 95% CI: 0.959-0.985), while no significant association was observed between sleep duration and telomere length. Furthermore, a suggestive association was found between moderate-to-vigorous physical activity and longer telomere length (OR: 1.680; 95% CI: 1.115-2.531). In multivariable MR analyses, adjusting for potential mediators such as body mass index, type 2 diabetes, alcohol consumption, and alcohol use disorder, the associations of lifetime smoking and insomnia with telomere length remained robust.ConclusionOur findings suggest that smoking and insomnia may contribute to telomere shortening, while physical activity may play a role in telomere length maintenance. These findings underscore the importance of managing positive risk factors and adopting a healthy lifestyle to promote telomere health.

Dataset Information

Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.

Publications

Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.

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