Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.
Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.
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克罗恩病和溃疡性结肠炎表型的遗传决定因素：遗传关联研究。
DOI：
10.1016/s0140-6736(15)00465-1
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发表时间：
2016-01-09
期刊：
影响因子：
--
通讯作者：
Lees CW
中科院分区：
文献类型：
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作者：
Cleynen I;Boucher G;Jostins L;Schumm LP;Zeissig S;Ahmad T;Andersen V;Andrews JM;Annese V;Brand S;Brant SR;Cho JH;Daly MJ;Dubinsky M;Duerr RH;Ferguson LR;Franke A;Gearry RB;Goyette P;Hakonarson H;Halfvarson J;Hov JR;Huang H;Kennedy NA;Kupcinskas L;Lawrance IC;Lee JC;Satsangi J;Schreiber S;Théâtre E;van der Meulen-de Jong AE;Weersma RK;Wilson DC;International Inflammatory Bowel Disease Genetics Consortium;Parkes M;Vermeire S;Rioux JD;Mansfield J;Silverberg MS;Radford-Smith G;McGovern DP;Barrett JC;Lees CW
克罗恩病和溃疡性结肠炎是炎症性肠病的两种主要形式;治疗策略历来由这种二元分类确定。遗传学研究已经确定了163个炎症性肠病的易感基因座，大多数在克罗恩病和溃疡性结肠炎之间共享。我们进行了迄今为止最大的基因型关联研究，在广泛使用的炎症性肠病的临床亚表型中，目的是进一步了解疾病之间的生物学关系。本研究纳入了来自欧洲、北美和澳大拉西亚16个国家49个中心的患者。我们应用蒙特利尔炎症性肠病亚表型分类系统对34819例患者（19713例克罗恩病，14683例溃疡性结肠炎）进行免疫芯片基因分型。 我们测试了156 154个遗传变异的基因型-表型关联。 我们通过结合所有已知的炎症性肠病相关信息来总结特定表型的遗传风险总负荷，从而生成遗传风险评分。我们使用这些风险评分来检验结肠克罗恩病、回肠克罗恩病和溃疡性结肠炎在遗传上彼此不同的假设，并试图识别临床诊断和遗传风险特征之间不匹配的患者。质量控制后，初步分析包括29 838例患者（16 902例克罗恩病，12 597例溃疡性结肠炎）。 三个位点（NOD 2、MHC和MST 1 3 p21）与炎症性肠病的亚表型相关，主要是疾病部位（随时间基本固定;中位随访时间为10.5年）。在对发病地点和发病年龄进行调节后，与疾病行为（随时间发生显著变化）的遗传关联很少或没有。代表炎症性肠病所有已知风险等位基因的遗传风险评分显示出与疾病亚表型的强相关性（p= 1.65 × 10−78），即使排除NOD 2、MHC和3 p21（p= 9.23 × 10−18）。 基于遗传风险评分的预测模型强烈区分了结肠克罗恩病和回肠克罗恩病。我们的遗传风险评分还可以识别出少数具有不一致遗传风险特征的患者，这些患者在随访后更有可能修改诊断（p= 6.8 × 10−4）。 我们的数据支持炎症性肠病中的一系列疾病，由三组（回肠克罗恩病，结肠克罗恩病和溃疡性结肠炎）比目前定义的克罗恩病和溃疡性结肠炎更好地解释。疾病部位是患者疾病的内在方面，部分由基因决定，并且是疾病行为随时间变化的主要驱动因素。国际炎症性肠道疾病遗传学联盟成员资金来源（完整列表请参阅致谢）。
Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4). Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).