Pang Jack X Q, Kheirkhahrahimabadi Hengameh, Bindra Sunint, Bindra Gurmeet, Panaccione Remo, Eksteen Bertus, Kaplan Gilaad G, Nasser Yasmin, Beck Paul L, Jijon Humberto B
Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
Current Address: Aspen Woods Clinic, Calgary, Alberta, Canada.
J Can Assoc Gastroenterol. 2020 Feb 3;4(2):65-72. doi: 10.1093/jcag/gwaa002. eCollection 2021 Apr.
Crohn's disease (CD) and ulcerative colitis (UC) demonstrate considerable phenotypic heterogeneity and course. Accurate predictors of disease behaviour are lacking. The contribution of genetics and specific polymorphisms is widely appreciated; however, their cumulative effect(s) upon disease behaviour remains poorly understood. Here, we investigate the relationship between genetic burden and disease phenotype in a Canadian inflammatory bowel disease (IBD) Cohort.
We retrospectively examined a cohort of CD and UC patients recruited from a single tertiary referral center genotyped using a Goldengate Illumina platform. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for 151 IBD-risk loci was calculated and evaluated for phenotypic associations.
Among CD patients, higher GRS was associated with earlier onset of disease (regression coefficient -2.19, 95% confidence interval [CI] -3.77 to -0.61, = 0.007), ileal disease (odds ratio [OR] 1.45), stricturing/penetrating disease (OR 1.72), perianal disease (OR 1.57) and bowel resection (OR 1.66). Higher GRS was associated with use of anti-tumor necrosis factor (TNF) ( < 0.05) but not immunomodulators. Interestingly, we could not demonstrate an association between higher GRS and family history of IBD (OR 1.27, = 0.07). Onset of disease remained statistically significant for never smokers ( = 0.03) but not ever smokers ( = 0.13). For UC, having a higher GRS did not predict the age of diagnosis nor was it predictive of UC disease extent ( = 0.18), the need for surgery ( = 0.74), nor medication use (immunomodulators = 0.53, anti-TNF = 0.49). We could not demonstrate an association between increased GRS and having a family history of IBD in the UC group.
Increasing genetic burden is associated with early age of diagnosis in CD and may be useful in predicting disease behaviour in CD but not UC.
克罗恩病（CD）和溃疡性结肠炎（UC）表现出相当大的表型异质性和病程差异。目前缺乏疾病行为的准确预测指标。遗传学及特定基因多态性的作用已得到广泛认可；然而，它们对疾病行为的累积效应仍知之甚少。在此，我们在一个加拿大炎症性肠病（IBD）队列中研究基因负担与疾病表型之间的关系。
我们回顾性研究了一组从单一三级转诊中心招募的CD和UC患者，这些患者使用Illumina金标准平台进行基因分型。计算并评估了包含151个IBD风险位点的关联强度（对数比值比）和等位基因剂量的遗传风险评分（GRS）与表型的相关性。
在CD患者中，较高的GRS与疾病较早发病相关（回归系数-2.19，95%置信区间[CI]-3.77至-0.61，P = 0.007）、回肠疾病（比值比[OR]1.45）、狭窄/穿透性疾病（OR 1.72）、肛周疾病（OR 1.57）及肠切除术（OR 1.66）。较高的GRS与使用抗肿瘤坏死因子（TNF）相关（P < 0.05），但与免疫调节剂无关。有趣的是，我们未能证明较高的GRS与IBD家族史之间存在关联（OR 1.27，P = 0.07）。疾病发病在从不吸烟者中仍具有统计学意义（P = 0.03），但在曾经吸烟者中无统计学意义（P = 0.13）。对于UC，较高的GRS既不能预测诊断年龄，也不能预测UC疾病范围（P = 0.18）、手术需求（P = 0.74）及药物使用情况（免疫调节剂P = 0.53，抗TNF P = 0.49）。我们未能证明UC组中GRS升高与IBD家族史之间存在关联。
基因负担增加与CD的早期诊断相关，可能有助于预测CD而非UC的疾病行为。
