Genetically Predicted Adiposity, Diabetes, and Lifestyle Factors in Relation to Diverticular Disease

Abstract

Higher exposure Lower exposure Mendelian randomization design Obesity Type 2 diabetes Smoking Diverticular disease data from • FinnGen (10 978 cases and 149 001 controls) • UK Biobank (12 662 cases and 348 532 controls) Results and conclusions Coffee intake Alcohol intake risk risk risk Analysis • Inverse-variance weighted method • Weighted median method • MR-Egger method • MR-PRESSO method • Contamination mixture method Random allocation of effect alleles BACKGROUND & AIMS:Adiposity, type 2 diabetes, alcohol and coffee consumption, and smoking have been examined in relation to diverticular disease in observational studies. We conducted a Mendelian randomization study to assess the causality of these associations. METHODS:Independent genetic instruments associated with the studied exposures at genome-wide significance were obtained from published genome-wide association studies. Summary-level data for the exposure-associated single nucleotide polymorphisms with diverticular disease were available in the FinnGen consortium (10,978 cases and 149,001 noncases) and the UK Biobank study (12,662 cases and 348,532 noncases). RESULTS:Higher genetically predicted body mass index and genetic liability to type 2 diabetes and smoking initiation were associated with an increased risk of diverticular disease in metaanalyses of results from the two studies. The combined odds ratio of diverticular disease was 1.23 (95% confidence interval [CI], 1.14-1.33; P < .001) for a 1-standard deviation (~4.8 kg/m 2 ) increase in body mass index, 1.04 (95% CI, 1.01-1.07; P ¼ .007) for a 1-unit increase in logtransformed odds ratio of type 2 diabetes, and 1.21 (95% CI, 1.12-1.30; P < .001) for a 1standard deviation increase in prevalence of smoking initiation. Coffee consumption was not associated with diverticular disease, whereas the association for alcohol consumption largely differed between the 2 studies.

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.…”

Type 2 diabetes and risk of diverticular disease: a Danish cohort study

“…None of the previous studies reporting an increased risk of diverticular disease in patients with diabetes [6][7][8] included adjustment for modifiable risk factors, including one study reporting an increased risk of diverticular disease in patients with a genetic liability to type 2 diabetes. 15 It is possible that the findings of these studies would have changed had they included adjustment for modifiable risk factors, most notably BMI. In fact, all studies suggesting that diabetes decreased or had no impact on the risk of diverticular disease included a measure of at least BMI, 9 11-14 with the exception of Nikberg et al 10 Another possible explanation for the ambiguous association is that diabetes may not be associated with the formation of diverticula per se, but can affect complication occurrence and thus the discovery of the disease.…”

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.…”