Smoking has been associated with opposing risks of ulcerative colitis and Crohn’s disease. Whether these observational associations reflect actual causal associations, confounding, or reverse causation is unclear. Using a Mendelian randomization approach, we tested the hypothesis that smoking protects against ulcerative colitis and is a cause of Crohn’s disease. We included 118,683 white Danes aged ≥ 20 from the Copenhagen General Population Study (2003–2015) and the Copenhagen City Heart Study (1991–94 and 2001–03). During follow-up until 2018, we investigated the association of smoking and CHRNA3 rs1051730, where the T-allele is strongly associated with nicotine dependence, with risk of ulcerative colitis and Crohn’s disease. We identified 1312 cases of ulcerative colitis and 671 cases of Crohn’s disease. Compared to never-smokers, multivariable adjusted hazard ratios (HRs) for ulcerative colitis were 1.69(95% confidence interval [CI] 1.32–2.15) in former smokers and 2.27(1.74–2.96) in current smokers. Corresponding HRs for Crohn’s disease were 1.31(0.93–1.84) and 1.93(1.34–2.78), respectively. Among ever-smokers when compared to non-carriers of the CHRNA3 rs1051730 T-allele, age and sex adjusted HRs for risk of ulcerative colitis were 1.03(95%CI 0.89–1.18) in heterozygotes and 0.91(0.72–1.16) in homozygotes. Corresponding HRs for Crohn’s disease were 1.05(0.87–1.28) and 1.02(0.74–1.41), respectively. In a meta-analysis combined with UK Biobank, there was no evidence that CHRNA3 rs1051730 was associated with risk of ulcerative colitis or Crohn’s disease. In conclusion, current versus never-smoking was associated with unexpected 2.3-fold risk of ulcerative colitis and expected 1.9-fold risk of Crohn’s disease in prospective analyses; however, genetic evidence of lifelong increased smoking intensity did not support causal relationships.

吸烟与溃疡性结肠炎和克罗恩病的相反风险有关。这些观察关联是否反映了实际的因果关联、混淆或反向因果关系尚不清楚。使用孟德尔随机化方法，我们检验了吸烟可以预防溃疡性结肠炎并且是克罗恩病病因的假设。我们纳入了来自哥本哈根一般人口研究（2003-2015）和哥本哈根市心脏研究（1991-94 和 2001-03）的 118,683 名 ≥ 20 岁的丹麦白人。在随访至 2018 年期间，我们调查了吸烟与CHRNA3的关系rs1051730，其中 T 等位基因与尼古丁依赖密切相关，具有溃疡性结肠炎和克罗恩病的风险。我们确定了 1312 例溃疡性结肠炎和 671 例克罗恩病。与从不吸烟者相比，溃疡性结肠炎的多变量调整风险比 (HRs) 在前吸烟者中为 1.69（95% 置信区间 [CI] 1.32-2.15），在当前吸烟者中为 2.27（1.74-2.96）。克罗恩病的相应 HR 分别为 1.31（0.93-1.84）和 1.93（1.34-2.78）。与非CHRNA3携带者相比，在吸烟者中rs1051730 T 等位基因、年龄和性别调整后的溃疡性结肠炎风险 HR 在杂合子中为 1.03（95%CI 0.89-1.18），在纯合子中为 0.91（0.72-1.16）。克罗恩病的相应 HR 分别为 1.05（0.87-1.28）和 1.02（0.74-1.41）。在一项联合英国生物银行的荟萃分析中，没有证据表明CHRNA3 rs1051730与溃疡性结肠炎或克罗恩病的风险相关。总之，在前瞻性分析中，目前与从不吸烟相比，溃疡性结肠炎的风险增加了 2.3 倍，克罗恩病风险增加了 1.9 倍。然而，终生吸烟强度增加的遗传证据并不支持因果关系。