Adiposity, diabetes, lifestyle factors and risk of gastroesophageal reflux disease: a Mendelian randomization study

Abstract

Adiposity, diabetes, and lifestyle factors are linked to gastroesophageal reflux disease (GERD) in observational studies. We conducted a two-sample Mendelian randomization analysis to determine whether those associations are causal. Independent genetic variants associated with body mass index (BMI), waist circumference (with and without adjustment for BMI), type 2 diabetes, smoking, and alcohol, coffee and caffeine consumption at the genome-wide significance level were selected as instrumental variables. Summary-level data for GERD were available from a genome-wide association meta-analysis of 71,522 GERD cases and 261,079 controls of European descent from the UK Biobank and QSkin Sun and Health studies. The odds ratio (OR) of GERD was 1.49 (95% confidence interval (CI), 1.40–1.60) for one standard deviation (SD) increase in BMI, 1.07 (95% CI, 1.04–1.10) for one-unit increase in log-transformed OR of type 2 diabetes, and 1.41 (95% CI, 1.31–1.52) for one SD increase in prevalence of smoking initiation. There were suggestive associations with GERD for higher genetically predicted waist circumference (OR per one SD increase, 1.14, 95% CI, 1.02–1.26) and caffeine consumption (OR per 80 mg increase, 1.08, 95% CI, 1.02–1.15). Genetically predicted waist circumference adjusted for BMI, alcohol or coffee consumption was not associated GERD. This study suggests causal roles of adiposity, diabetes, and smoking, and a possible role of high caffeine consumption in the development of GERD.

Genetic estimation of correlations and causalities between multifaceted modifiable factors and gastro-oesophageal reflux disease

“…Previous MR studies examined the causal associations between smoking initiation, asthma, type 2 diabetes, BMI, waist circumference, waist-to-hip ratio, standing height, and the risk of GORD primarily among European-ancestry individuals in the UKB database ( 16 , 35 – 37 ), whose MR findings were also replicated in this study with larger-scale GORD GWAS datasets from Neale Lab and FinnGen consortium. In this study, we systematically examined causal associations between 66 exposures across 6 modifiable pathways and the risk of GORD in order to comprehensively elucidate the causal modifiable factors that were associated with the risk of GORD.…”

“…Thirdly, genetic variants associated with specific exposures will index lifetime differences and thus produce causal estimates that are unsusceptible to the attenuation by errors (regression dilution bias) ( 15 ). To date, central obesity indicators (BMI, waist circumference, hip circumference) and daily habits (smoking and alcohol consumption) have been examined for their causal effects on the risk of GORD using MR analysis ( 16 ). However, there have been no studies evaluating factors that are causally associated with the risk of GORD as comprehensively as possible.…”

Appraising the causal role of smoking in multiple diseases: A systematic review and meta-analysis of Mendelian randomization studies

“…After exclusion of studies using overlapping or same outcome data, 29 articles based on non-overlapping populations were eligible for inclusion in one or more meta-analyses. The number of studies included in each outcome category was seven for circulatory system diseases, 4 , 5 , 6 , 7 , 8 , 9 , 10 six for digestive system diseases, 11 , 12 , 13 , 14 , 15 , 16 six for nervous system diseases, 17 , 18 , 19 , 20 , 21 three for musculoskeletal system outcomes, 22 , 23 , 24 two for endocrine and metabolic diseases, 25 , 26 two for eye diseases, 27 , 28 and four for neoplasms. 29 , 30 , 31 , 32 In addition to the included studies, 123 de novo MR analyses ( n =51 for smoking initiation, n = 72 for lifetime smoking) were conducted.…”

“…During the last few years, the potential causal association between smoking and risk of different diseases has been investigated using the Mendelian randomization (MR) approach. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 MR is a method that utilizes genetic variants associated with a difference in the exposure (e.g., smoking liability) as instrumental variable for the exposure to determine the causal role of the exposure in the development of disease. 33 The MR design mitigates confounding because genetic alleles are randomly allocated when passed from parents to offspring and therefore usually not related to other risk factors.…”

Birthweight, Childhood Obesity, Adulthood Obesity and Body Compositions, and Gastrointestinal Diseases: A Mendelian Randomization Study

“…Since genetic variants are randomly assorted at conception and cannot be modified by the onset of disease, MR investigation is less likely to be affected by confounding and reverse causality. Even though previous MR studies identified the associations of adulthood body mass index (BMI) and waist-hip ratio (WHR) with the risk of gastroesophageal reflux, esophageal cancer, gastric cancer, diverticular disease, non-alcoholic liver disease, liver cancer, cholelithiasis, and pancreatic cancer (15)(16)(17)(18), the MR associations of adulthood obesity with other gastrointestinal diseases, like peptic ulcer, irritable bowel syndrome and pancreatitis, remains unestablished. In addition, the associations of other obesity-related traits with the risk of gastrointestinal disease have not been scarcely investigated.…”