Sun Yuanlin, Cao Xueyuan, Cao Donghui, Cui Yingnan, Su Kaisheng, Jia Zhifang, Wu Yanhua, Jiang Jing
Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Department of Clinical Epidemiology, The First Hospital of Jilin University, Changchun, Jilin, China.
Front Nutr. 2022 Nov 1;9:1009122. doi: 10.3389/fnut.2022.1009122. eCollection 2022.
Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal dysfunction that significantly affects the quality of daily life, and health interventions are challenging to prevent the risk of GORD. In this study, we used Mendelian randomization framework to genetically determine the causal associations between multifaceted modifiable factors and the risk of GORD.
Sixty-six exposures with available instrumental variables (IVs) across 6 modifiable pathways were included in the univariable MR analysis (UVMR). Summary-level genome-wide association studies (GWAS) datasets for GORD were retrieved from the Neale Lab (GORD , Ncases = 29975, Ncontrols = 390556) and FinnGen (GORD , Ncases = 13141, Ncontrols = 89695). Using the METAL software, meta-analysis for single nucleotide polymorphisms (SNPs) from GORD and GORD was conducted with an inverse variance weighted (IVW) fixed-effect model. Moreover, we leveraged partition around medoids (PAM) clustering algorithm to cluster genetic correlation subtypes, whose hub exposures were conditioned for multivariable MR (MVMR) analyses. -values were adjusted with Bonferroni multiple comparisons.
Significant causal associations were identified between 26 exposures (15 risk exposures and 11 protective exposures) and the risk of GORD. Among them, 13 risk exposures [lifetime smoking, cigarette consumption, insomnia, short sleep, leisure sedentary behavior (TV watching), body mass index (BMI), body fat percentage, whole body fat mass, visceral adipose tissue, waist circumference, hip circumference, major depressive disorder, and anxious feeling], and 10 protective exposures (leisure sedentary behavior (computer use), sitting height, hand grip strength (left and right), birth weight, life satisfaction, positive affect, income, educational attainment, and intelligence) showed novel significant causal associations with the risk of GORD. Moreover, 13 exposures still demonstrated independent associations with the risk of GORD following MVMR analyses conditioned for hub exposures (educational attainment, smoking initiation and BMI). In addition, 12 exposures showed suggestive causal associations with the risk of GORD.
This study systematically elucidated the modifiable factors causally associated with the risk of GORD from multifaceted perspectives, which provided implications for prevention and treatment of GORD.
胃食管反流病（GORD）是一种常见的胃肠功能障碍，严重影响日常生活质量，而健康干预措施在预防GORD风险方面具有挑战性。在本研究中，我们使用孟德尔随机化框架从基因层面确定多方面可改变因素与GORD风险之间的因果关联。
单变量孟德尔随机化分析（UVMR）纳入了6条可改变途径中的66种具有可用工具变量（IVs）的暴露因素。从Neale实验室（GORD，病例数=29975，对照数=390556）和芬兰基因库（GORD，病例数=13141，对照数=89695）检索GORD的汇总水平全基因组关联研究（GWAS）数据集。使用METAL软件，采用逆方差加权（IVW）固定效应模型对来自GORD和GORD的单核苷酸多态性（SNPs）进行荟萃分析。此外，我们利用围绕中心点划分（PAM）聚类算法对遗传相关亚型进行聚类，其核心暴露因素用于多变量孟德尔随机化（MVMR）分析。P值采用Bonferroni多重比较进行校正。
确定了26种暴露因素（15种风险暴露因素和11种保护暴露因素）与GORD风险之间存在显著的因果关联。其中，13种风险暴露因素[终生吸烟、香烟消费量、失眠、睡眠不足、休闲久坐行为（看电视）、体重指数（BMI）、体脂百分比、全身脂肪量、内脏脂肪组织、腰围、臀围、重度抑郁症和焦虑情绪]，以及10种保护暴露因素[休闲久坐行为（使用电脑）、坐高、握力（左右）、出生体重、生活满意度、积极情绪、收入、教育程度和智力]与GORD风险存在新的显著因果关联。此外，在以核心暴露因素（教育程度、开始吸烟和BMI）为条件进行MVMR分析后，13种暴露因素仍显示与GORD风险存在独立关联。另外，12种暴露因素显示与GORD风险存在提示性因果关联。
本研究从多方面系统阐明了与GORD风险存在因果关联的可改变因素，为GORD的预防和治疗提供了启示。
