Modeling the Causal Role of DNA Methylation in the Association Between Cigarette Smoking and Inflammation in African Americans: A 2-Step Epigenetic Mendelian Randomization Study

Abstract Background DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated. Methods We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer. Results Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk. Conclusions The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.

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The causal role of obesity in diabetic kidney disease —evidence from a Mendelian randomization study

Nature Reviews Endocrinology ◽

10.1038/nrendo.2015.159 ◽

2015 ◽

Vol 11 (11) ◽

pp. 632-632

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Mendelian Randomization ◽

Causal Role ◽

Diabetic Kidney

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The Causal Role of Cigarette Smoking in Bladder Cancer Initiation and Progression, and the Role of Urologists in Smoking Cessation

The Journal of Urology ◽

10.1016/j.juro.2008.03.045 ◽

2008 ◽

Vol 180 (1) ◽

pp. 31-37 ◽

Cited By ~ 73

Author(s):

Seth A. Strope ◽

James E. Montie

Keyword(s):

Bladder Cancer ◽

Smoking Cessation ◽

Cigarette Smoking ◽

Causal Role ◽

Cancer Initiation

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Estimating the causal role of C-reactive protein in coronary heart disease: Collaborative mendelian randomization analysis

Atherosclerosis ◽

10.1016/j.atherosclerosis.2010.08.024 ◽

2010 ◽

Vol 213 (1) ◽

pp. e12

Author(s):

F. Wensley

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Mendelian Randomization ◽

Causal Role ◽

C Reactive Protein ◽

Reactive Protein ◽

Mendelian Randomization Analysis ◽

Randomization Analysis

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CD28 Genetic Variants Increase Susceptibility to Diabetic Kidney Disease in Chinese Patients with Type 2 Diabetes: A Cross-Sectional Case Control Study

Mediators of Inflammation ◽

10.1155/2021/5521050 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Yangyang Li ◽

Li Jin ◽

Jing Yan ◽

Hong Zhang ◽

Rong Zhang ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Mendelian Randomization ◽

Costimulatory Molecule ◽

Causal Role ◽

Chinese Patients ◽

Diabetic Kidney ◽

Mendelian Randomization Analysis ◽

Randomization Analysis

Few studies have illuminated the genetic role of T cell costimulatory molecule CD28/CD80/CTLA4 variants in diabetic kidney disease (DKD) susceptibility. We aimed to investigate the causal role of genetic polymorphisms in CD28/CD80/CTLA4 with DKD susceptibility in patients with T2DM. A total of 3253 patients with T2DM were recruited for genotyping: including 204 DKD patients and 371 controls in stage 1 and 819 DKD patients and 563 controls in stage 2; besides, 1296 T2DM patients were selected for the analysis of association between loci and DKD-related traits. A subset of 227 T2DM patients (118 patients with DKD and 109 patients without DKD) from the total population above were selected to assess serum soluble CD28 (sCD28) levels. Then, we performed a candidate gene association study to identify single-nucleotide polymorphisms (SNPs) associated with DKD susceptibility and further used those SNPs to perform Mendelian randomization analyses of serum sCD28 level and DKD susceptibility. Under additive genetic models, CD28-rs3116494 ( OR = 1.29 [95% CI 1.11, 1.51], P = 0.0011 ) and CD80-rs3850890 ( OR = 1.16 [95% CI 1.02, 1.31], P = 0.0283 ) were associated with DKD susceptibility adjusted for age, gender, body mass index (BMI), duration of diabetes, and HbA1c. CD28-rs3116494 was associated with serum sCD28 level ( β = 0.26 [95% CI 0.08, 0.44], P = 0.0043 ). The Mendelian randomization analysis showed that CD28-rs3116494 played a causal role in DKD by influencing serum sCD28 levels ( β = 1.15 [95% CI 0.46, 1.83], P = 0.0010 ). In conclusion, we identified that two novel SNPs, CD28-rs3116494 and CD80-rs3850890, were associated with DKD susceptibility. Using the Mendelian randomization analysis, our study provided evidence for a causal relationship between serum CD28 levels and DKD with T2DM in the Chinese population.

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Body mass index and mortality in UK Biobank: revised estimates using Mendelian randomization

10.1101/281436 ◽

2018 ◽

Cited By ~ 2

Author(s):

Kaitlin H Wade ◽

David Carslake ◽

Naveed Sattar ◽

George Davey Smith ◽

Nicholas J Timpson

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

Causal Effect ◽

Genotypic Variation ◽

Lung Cancer Mortality ◽

Causal Role ◽

Uk Biobank ◽

All Cause Mortality

AbstractObjectiveObtain estimates of the causal relationship between different levels of body mass index (BMI) and mortality.MethodsMendelian randomization (MR) was conducted using genotypic variation reliably associated with BMI to test the causal effect of increasing BMI on all-cause and cause-specific mortality in participants of White British ancestry in UK Biobank.ResultsMR analyses supported existing evidence for a causal association between higher levels of BMI and greater risk of all-cause mortality (hazard ratio (HR) per 1kg/m2: 1.02; 95% CI: 0.97,1.06) and mortality from cardiovascular diseases (HR: 1.12; 95% CI: 1.02, 1.23), specifically coronary heart disease (HR: 1.19; 95% CI: 1.05, 1.35) and those other than stroke/aortic aneurysm (HR: 1.13; 95% CI: 0.93, 1.38), stomach cancer (HR: 1.30; 95% CI: 0.91, 1.86) and oesophageal cancer (HR: 1.08; 95% CI: 0.84, 1.38), and with decreased risk of lung cancer mortality (HR: 0.97; 95% CI: 0.84, 1.11). Sex-stratified analyses supported a causal role of higher BMI in increasing the risk of mortality from bladder cancer in males and other causes in females, but in decreasing the risk of respiratory disease mortality in males. The characteristic J-shaped observational association between BMI and mortality was visible with MR analyses but with a smaller value of BMI at which mortality risk was lowest and apparently flatter over a larger range of BMI.ConclusionResults support a causal role of higher BMI in increasing the risk of all-cause mortality and mortality from other causes. However, studies with greater numbers of deaths are needed to confirm the current findings.

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