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Abstract：
Previous studies have reported associations of Crohn\'s disease (CD) and ulcerative colitis (UC) with the risks of extraintestinal cancers, but the causality remains unclear.
Using genetic variations robustly associated with CD and UC extracted from genome-wide association studies (GWAS) as instrumental variables. Nine types of extraintestinal cancers of European and Asian populations were selected as outcomes. We used the inverse variance weighted method as the primary approach for two-sample Mendelian randomization analysis. Sensitivity analyses were carried out to evaluate the reliability of our findings.
In the European population, we found that CD showed a potential causal relationship with pancreatic cancer (OR: 1.1042; 95% CI: 1.0087-1.2088; P=0.0318). Meanwhile, both CD (outliers excluded: OR: 1.0208; 95% CI: 1.0079-1.0339; P=0.0015) and UC (outliers excluded: OR: 1.0220; 95% CI: 1.0051-1.0393; P=0.0108) were associated with a slight increase in breast cancer risk. Additionally, UC exhibited a potential causal effect on cervical cancer (outliers excluded: OR: 1.1091; 95% CI: 1.0286-1.1960; P=0.0071). In the East Asian population, CD had significant causal effects on pancreatic cancer (OR: 1.1876; 95% CI: 1.0741-1.3132; P=0.0008) and breast cancer (outliers excluded: OR: 0.9452; 95% CI: 0.9096-0.9822; P=0.0040). For UC, it exhibited significant causal associations with gastric cancer (OR: 1.1240; 95% CI: 1.0624-1.1891; P=4.7359×10-5), bile duct cancer (OR: 1.3107; 95% CI: 1.0983-1.5641; P=0.0027), hepatocellular carcinoma (OR: 1.2365; 95% CI: 1.1235-1.3608; P=1.4007×10-5) and cervical cancer (OR: 1.3941; 95% CI: 1.1708-1.6599; P=0.0002), as well as a potential causal effect on lung cancer (outliers excluded: OR: 1.1313; 95% CI: 1.0280-1.2449; P=0.0116).
Our study provided evidence that genetically predicted CD may be a risk factor for pancreatic and breast cancers in the European population, and for pancreatic cancer in the East Asian population. Regarding UC, it may be a risk factor for cervical and breast cancers in Europeans, and for gastric, bile duct, hepatocellular, lung, and cervical cancers in East Asians. Therefore, patients with CD and UC need to emphasize screening and prevention of site-specific extraintestinal cancers.
Using genetic variations robustly associated with CD and UC extracted from genome-wide association studies (GWAS) as instrumental variables. Nine types of extraintestinal cancers of European and Asian populations were selected as outcomes. We used the inverse variance weighted method as the primary approach for two-sample Mendelian randomization analysis. Sensitivity analyses were carried out to evaluate the reliability of our findings.
In the European population, we found that CD showed a potential causal relationship with pancreatic cancer (OR: 1.1042; 95% CI: 1.0087-1.2088; P=0.0318). Meanwhile, both CD (outliers excluded: OR: 1.0208; 95% CI: 1.0079-1.0339; P=0.0015) and UC (outliers excluded: OR: 1.0220; 95% CI: 1.0051-1.0393; P=0.0108) were associated with a slight increase in breast cancer risk. Additionally, UC exhibited a potential causal effect on cervical cancer (outliers excluded: OR: 1.1091; 95% CI: 1.0286-1.1960; P=0.0071). In the East Asian population, CD had significant causal effects on pancreatic cancer (OR: 1.1876; 95% CI: 1.0741-1.3132; P=0.0008) and breast cancer (outliers excluded: OR: 0.9452; 95% CI: 0.9096-0.9822; P=0.0040). For UC, it exhibited significant causal associations with gastric cancer (OR: 1.1240; 95% CI: 1.0624-1.1891; P=4.7359×10-5), bile duct cancer (OR: 1.3107; 95% CI: 1.0983-1.5641; P=0.0027), hepatocellular carcinoma (OR: 1.2365; 95% CI: 1.1235-1.3608; P=1.4007×10-5) and cervical cancer (OR: 1.3941; 95% CI: 1.1708-1.6599; P=0.0002), as well as a potential causal effect on lung cancer (outliers excluded: OR: 1.1313; 95% CI: 1.0280-1.2449; P=0.0116).
Our study provided evidence that genetically predicted CD may be a risk factor for pancreatic and breast cancers in the European population, and for pancreatic cancer in the East Asian population. Regarding UC, it may be a risk factor for cervical and breast cancers in Europeans, and for gastric, bile duct, hepatocellular, lung, and cervical cancers in East Asians. Therefore, patients with CD and UC need to emphasize screening and prevention of site-specific extraintestinal cancers.
摘要：
■先前的研究报道了克罗恩病（CD）和溃疡性结肠炎（UC）与肠外癌症风险的关联，但因果关系尚不清楚。
■使用从全基因组关联研究（GWAS）中提取的与CD和UC强烈相关的遗传变异作为工具变量。选择了欧洲和亚洲人群的九种类型的肠外癌症作为结果。我们使用逆方差加权方法作为双样本孟德尔随机化分析的主要方法。进行了敏感性分析以评估我们发现的可靠性。
■在欧洲人口中，我们发现CD与胰腺癌有潜在的因果关系(OR:1.1042;95%CI:1.0087-1.2088;P=0.0318).同时,CD(不包括异常值:OR:1.0208;95%CI:1.0079-1.0339;P=0.0015)和UC(不包括异常值:OR:1.0220;95%CI:1.0051-1.0393;P=0.0108)均与乳腺癌风险略有增加相关.此外,UC对宫颈癌具有潜在的因果效应（异常值排除：OR：1.1091；95％CI：1.0286-1.1960；P=0.0071）。在东亚人口中，CD对胰腺癌(OR:1.1876;95%CI:1.0741-1.3132;P=0.0008)和乳腺癌(异常值排除:OR:0.9452;95%CI:0.9096-0.9822;P=0.0040)有显著的因果效应。对于UC，与胃癌有显著的因果关系(OR:1.1240;95%CI:1.0624-1.1891;P=4.7359×10-5),胆管癌(OR:1.3107;95%CI:1.0983-1.5641;P=0.0027),肝细胞癌（OR：1.2365;95％CI：1.1235-1.3608;P=1.4007×10-5）和宫颈癌（OR：1.3941;95％CI：1.1708-1.6599;P=0.0002），以及对肺癌的潜在因果效应(排除异常值:OR:1.1313;95%CI:1.0280-1.2449;P=0.0116)。
■我们的研究提供了证据，表明基因预测的CD可能是欧洲人群中胰腺癌和乳腺癌的危险因素，和东亚人群的胰腺癌。关于UC，这可能是欧洲人宫颈癌和乳腺癌的危险因素，对于胃，胆管,肝细胞，肺，和东亚人的宫颈癌。因此,CD和UC患者需要强调特定部位的肠外癌症的筛查和预防.
■使用从全基因组关联研究（GWAS）中提取的与CD和UC强烈相关的遗传变异作为工具变量。选择了欧洲和亚洲人群的九种类型的肠外癌症作为结果。我们使用逆方差加权方法作为双样本孟德尔随机化分析的主要方法。进行了敏感性分析以评估我们发现的可靠性。
■在欧洲人口中，我们发现CD与胰腺癌有潜在的因果关系(OR:1.1042;95%CI:1.0087-1.2088;P=0.0318).同时,CD(不包括异常值:OR:1.0208;95%CI:1.0079-1.0339;P=0.0015)和UC(不包括异常值:OR:1.0220;95%CI:1.0051-1.0393;P=0.0108)均与乳腺癌风险略有增加相关.此外,UC对宫颈癌具有潜在的因果效应（异常值排除：OR：1.1091；95％CI：1.0286-1.1960；P=0.0071）。在东亚人口中，CD对胰腺癌(OR:1.1876;95%CI:1.0741-1.3132;P=0.0008)和乳腺癌(异常值排除:OR:0.9452;95%CI:0.9096-0.9822;P=0.0040)有显著的因果效应。对于UC，与胃癌有显著的因果关系(OR:1.1240;95%CI:1.0624-1.1891;P=4.7359×10-5),胆管癌(OR:1.3107;95%CI:1.0983-1.5641;P=0.0027),肝细胞癌（OR：1.2365;95％CI：1.1235-1.3608;P=1.4007×10-5）和宫颈癌（OR：1.3941;95％CI：1.1708-1.6599;P=0.0002），以及对肺癌的潜在因果效应(排除异常值:OR:1.1313;95%CI:1.0280-1.2449;P=0.0116)。
■我们的研究提供了证据，表明基因预测的CD可能是欧洲人群中胰腺癌和乳腺癌的危险因素，和东亚人群的胰腺癌。关于UC，这可能是欧洲人宫颈癌和乳腺癌的危险因素，对于胃，胆管,肝细胞，肺，和东亚人的宫颈癌。因此,CD和UC患者需要强调特定部位的肠外癌症的筛查和预防.
