Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study.

Gastro-oesophageal reflux disease (GORD) is associated with multiple risk factors but determining causality is difficult. We used a genetic approach [Mendelian randomization (MR)] to identify potential causal modifiable risk factors for GORD. We used data from 451 097 European participants in the UK Biobank and defined GORD using hospital-defined ICD10 and OPCS4 codes and self-report data (N = 41 024 GORD cases). We tested observational and MR-based associations between GORD and four adiposity measures [body mass index (BMI), waist-hip ratio (WHR), a metabolically favourable higher body-fat percentage and waist circumference], smoking status, smoking frequency and caffeine consumption. Observationally, all adiposity measures were associated with higher odds of GORD. Ever and current smoking were associated with higher odds of GORD. Coffee consumption was associated with lower odds of GORD but, among coffee drinkers, more caffeinated-coffee consumption was associated with higher odds of GORD. Using MR, we provide strong evidence that higher WHR and higher WHR adjusted for BMI lead to GORD. There was weak evidence that higher BMI, body-fat percentage, coffee drinking or smoking caused GORD, but only the observational effects for BMI and body-fat percentage could be excluded. This MR estimated effect for WHR equates to a 1.23-fold higher odds of GORD per 5-cm increase in waist circumference. These results provide strong evidence that a higher waist-hip ratio leads to GORD. Our study suggests that central fat distribution is crucial in causing GORD rather than overall weight.

Green HD ，Beaumont RN ，Wood AR ，Hamilton B ，Jones SE ，Goodhand JR ，Kennedy NA ，Ahmad T ，Yaghootkar H ，Weedon MN ，Frayling TM ，Tyrrell J ... -  《-》

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

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.

Yuan S ，Larsson SC 《-》

Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease.

Emdin CA ，Khera AV ，Natarajan P ，Klarin D ，Zekavat SM ，Hsiao AJ ，Kathiresan S ... -  《-》

Estimating causality between smoking and abdominal obesity by Mendelian randomization.

Smokers tend to have a lower body weight than non-smokers, but also more abdominal fat. It remains unclear whether or not the relationship between smoking and abdominal obesity is causal. Previous Mendelian randomization (MR) studies have investigated this relationship by relying upon a single genetic variant for smoking heaviness. This approach is sensitive to pleiotropic effects and may produce imprecise causal estimates. We aimed to estimate causality between smoking and abdominal obesity using multiple genetic instruments. MR study using causal analysis using summary effect estimates (CAUSE) and latent heritable confounder MR (LHC-MR) methods that instrument smoking using genome-wide data, and also two-sample MR (2SMR) methods. Genome-wide association studies (GWAS) summary statistics from participants of European ancestry, obtained from the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), Genetic Investigation of Anthropometric Traits (GIANT) Consortium and the UK Biobank. We used GWAS results for smoking initiation (n = 1 232 091), life-time smoking (n = 462 690) and smoking heaviness (n = 337 334) as exposure traits, and waist-hip ratio (WHR) and waist and hip circumferences (WC and HC) (n up to 697 734), with and without adjustment for body mass index (adjBMI), as outcome traits. Smoking initiation, life-time smoking, smoking heaviness, WHR, WC, HC, WHRadjBMI, WCadjBMI and HCadjBMI. Both CAUSE and LHC-MR indicated a positive causal effect of smoking initiation on WHR (0.13 [95% confidence interval (CI) = 0.10, 0.16 and 0.49 (0.41, 0.57), respectively] and WHRadjBMI (0.07 (0.03, 0.10) and 0.31 (0.26, 0.37). Similarly, they indicated a positive causal effect of life-time smoking on WHR [0.35 (0.29, 0.41) and 0.44 (0.38, 0.51)] and WHRadjBMI [0.18 (0.13, 0.24) and 0.26 (0.20, 0.31)]. In follow-up analyses, smoking particularly increased visceral fat. There was no evidence of a mediating role by cortisol or sex hormones. Smoking initiation and higher life-time smoking may lead to increased abdominal fat distribution. The increase in abdominal fat due to smoking is characterized by an increase in visceral fat. Thus, efforts to prevent and cease smoking can have the added benefit of reducing abdominal fat.

Carrasquilla GD ，García-Ureña M ，Romero-Lado MJ ，Kilpeläinen TO ... -  《-》

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

Bull CJ ，Bell JA ，Murphy N ，Sanderson E ，Davey Smith G ，Timpson NJ ，Banbury BL ，Albanes D ，Berndt SI ，Bézieau S ，Bishop DT ，Brenner H ，Buchanan DD ，Burnett-Hartman A ，Casey G ，Castellví-Bel S ，Chan AT ，Chang-Claude J ，Cross AJ ，de la Chapelle A ，Figueiredo JC ，Gallinger SJ ，Gapstur SM ，Giles GG ，Gruber SB ，Gsur A ，Hampe J ，Hampel H ，Harrison TA ，Hoffmeister M ，Hsu L ，Huang WY ，Huyghe JR ，Jenkins MA ，Joshu CE ，Keku TO ，Kühn T ，Kweon SS ，Le Marchand L ，Li CI ，Li L ，Lindblom A ，Martín V ，May AM ，Milne RL ，Moreno V ，Newcomb PA ，Offit K ，Ogino S ，Phipps AI ，Platz EA ，Potter JD ，Qu C ，Quirós JR ，Rennert G ，Riboli E ，Sakoda LC ，Schafmayer C ，Schoen RE ，Slattery ML ，Tangen CM ，Tsilidis KK ，Ulrich CM ，van Duijnhoven FJB ，van Guelpen B ，Visvanathan K ，Vodicka P ，Vodickova L ，Wang H ，White E ，Wolk A ，Woods MO ，Wu AH ，Campbell PT ，Zheng W ，Peters U ，Vincent EE ，Gunter MJ ... -  《BMC Medicine》