Alzheimer Prevention Program, BarcelonaBeta Brain Research Center (BBRC), Barcelona, Spain.
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
Am J Gastroenterol. 2019 Jun;114(6):893-899. doi: 10.14309/ajg.0000000000000219.
Several single-nucleotide polymorphisms (SNPs) have been associated with Barrett's esophagus (BE) risk. In addition, environmental factors including smoking, alcohol consumption, and heartburn increase BE risk. However, data on potential interactions between these genetic and environmental factors on BE risk are scant. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of BE, and potentially identify opportunities for targeted prevention and treatment. The objectives of this study were to examine the main effects and the potential effect modification between known genetic loci (SNPs) and established environmental risk factors for BE.
We performed a nested case-control study using data on 401 incident BE cases and 436 age-matched controls from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood and completed biennial questionnaires. Overall, we genotyped 46 SNPs identified in previous BE genome-wide association studies as well as SNPs in candidate genes related to BE susceptibility (i.e., related to excess body fat, fat distribution, factors associated with insulin resistance, and inflammatory mediators). A genetic risk score (GRS) was constructed to evaluate the combined effect of the selected SNPs on BE risk. Interactions between SNPs and BE risk factors were also assessed.
We observed a suggestive, but not statistically significant, association between our GRS and BE risk: a one-allele increase in the unweighted GRS increased the risk of BE by a factor of 1.20 (95% confidence interval = 1.00-1.44; P = 0.057). We did not observe any meaningful multiplicative interactions between smoking, alcohol consumption, or heartburn duration and BE genotypes. When we assessed the joint effect of weighted GRS and BE risk factors, we did not observe any significant interaction with alcohol and heartburn duration, whereas smoking showed a significant multiplicative interaction (P = 0.016).
Our results suggest that SNPs associated with BE at genome-wide significant levels can be combined into a GRS with a potential positive association with BE risk.
已有多项单核苷酸多态性（SNP）与 Barrett 食管（BE）风险相关。此外，包括吸烟、饮酒和胃灼热在内的环境因素也会增加 BE 的风险。然而，关于这些遗传和环境因素之间潜在相互作用与 BE 风险的数据却很少。了解基因和环境风险因素如何相互作用，可能为 BE 的病理生理学提供关键的见解，并有可能确定针对该疾病的预防和治疗机会。本研究的目的是检查已知遗传位点（SNP）与 BE 的既定环境风险因素之间的主要作用和潜在的效应修饰作用。
我们使用来自护士健康研究、护士健康研究 II 和健康专业人员随访研究队列的 401 例新发 BE 病例和 436 名年龄匹配对照的数据，进行了一项巢式病例对照研究。我们对先前 BE 全基因组关联研究中确定的 46 个 SNP 以及与 BE 易感性相关的候选基因中的 SNP（即与多余体脂、脂肪分布、与胰岛素抵抗相关的因素以及炎症介质相关的 SNP）进行了基因分型。构建了遗传风险评分（GRS），以评估选定 SNP 对 BE 风险的综合影响。还评估了 SNP 与 BE 风险因素之间的相互作用。
我们观察到 GRS 与 BE 风险之间存在提示性但无统计学意义的关联：未加权 GRS 中一个等位基因的增加使 BE 的风险增加了 1.20 倍（95%置信区间=1.00-1.44；P=0.057）。我们没有观察到吸烟、饮酒或胃灼热持续时间与 BE 基因型之间存在任何有意义的乘法相互作用。当我们评估加权 GRS 和 BE 风险因素的联合效应时，我们没有观察到与饮酒和胃灼热持续时间的任何显著相互作用，而吸烟则显示出显著的乘法相互作用（P=0.016）。
我们的结果表明，与 BE 具有全基因组显著关联的 SNP 可以组合成一个 GRS，该 GRS 与 BE 风险有潜在的正相关。
