Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study

Abstract

ObjectivesWe applied Mendelian randomization (MR) to investigate the causal associations of body mass index (BMI) and waist circumference (WC) with 19 gastrointestinal (GI) disorders.DesignMR study.SettingThe UK Biobank, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, FinnGen consortium, and genome-wide association studies.ParticipantsOverall, >400,000 UK Biobank participants, >170,000 participants of Finnish descent, and numerous consortia participants with predominantly European ancestry.InterventionsSingle-nucleotide polymorphisms associated with BMI and WC were used as instrumental variables to estimate the causal associations with the GI conditions.Main outcome measuresRisk of developing 19 GI diseasesResultsAfter correction for multiple testing (Bonferroni-corrected threshold of P<0.05/19) and testing for consistencies using several MR methods with varying assumptions (inverse variance weighted, weighted median, MR-Egger, and MR-PRESSO), genetically predicted BMI was associated with increased risks of non-alcoholic fatty liver disease (NAFLD), cholecystitis, cholelithiasis, and primary biliary cholangitis. The odds ratio (OR) per one standard deviation (SD) increased in genetically predicted BMI (4.77 kg/m2) from 1.22 (95% confidence interval [CI] 1.12–1.34; P<0.0001) for NAFLD to 1.65 (95% CI 1.31–2.06; P<0.0001) for cholecystitis. Genetically predicted WC was associated with increased risks of NAFLD, alcoholic liver disease (ALD), cholecystitis, cholelithiasis, colon cancer, and gastric cancer. ALD was associated with WC even after adjustment for alcohol consumption in multivariable MR analysis. The OR per 1 SD increased in genetically predicted WC (12.52 cm) from 1.41 (95% CI 1.17–1.70; P=0.0015) for gastric cancer to 1.74 (95% CI 1.21–1.78; P<0.0001) for cholelithiasis.ConclusionsHigher BMI and WC are causally associated with an increased risk of GI abnormalities, particularly of hepatobiliary organs (liver, biliary tract, and gallbladder) that are functionally related to fat metabolism. Abdominal obesity measured by WC might be more influential and relevant with a diverse span of GI diseases than BMI, highlighting a possible pathophysiological role of visceral abdominal fats in the development of GI disorders and cancers.Graphical Abstract

Visceral adipose tissue and risk of nonalcoholic fatty liver disease: A Mendelian randomization study

“…NAFLD data (1483 cases, 17,781 controls) was not from UKB or FinnGen study. In this study, genetically predicted BMI and WC were robustly associated with an increased risk of NAFLD 30 . BMI is not an index that can accurately measure abdominal obesity.…”

“…In this study, genetically predicted BMI and WC were robustly associated with an increased risk of NAFLD. 30 BMI is not an index that can accurately measure abdominal obesity. As an anthropological index for measuring abdominal obesity, WC cannot distinguish visceral fat from subcutaneous fat.…”

Association of bariatric surgery with indicated and unintended outcomes: An umbrella review and meta‐analysis for risk–benefit assessment

“…This substantial decrease in adipose tissue could explain our results, given that obesity has been identified as a causal risk factor for most of the outcomes presented in our study. Mendelian randomization studies have confirmed that increased adiposity is causally associated with an increased risk of CVDs, 38 GI diseases, 39,40 depression, 41 cancers, 42,43 and reproductive conditions 44 …”