Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.
Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.
复制标题
DOI：
10.1038/ng.3760
复制
发表时间：
2017-02
期刊：
影响因子：
30.8
通讯作者：
Barrett JC
中科院分区：
文献类型：
--
作者：
de Lange KM;Moutsianas L;Lee JC;Lamb CA;Luo Y;Kennedy NA;Jostins L;Rice DL;Gutierrez-Achury J;Ji SG;Heap G;Nimmo ER;Edwards C;Henderson P;Mowat C;Sanderson J;Satsangi J;Simmons A;Wilson DC;Tremelling M;Hart A;Mathew CG;Newman WG;Parkes M;Lees CW;Uhlig H;Hawkey C;Prescott NJ;Ahmad T;Mansfield JC;Anderson CA;Barrett JC
遗传关联研究已经确定了215个炎症性肠病的危险基因，揭示了其分子生物学的基本方面。我们对25,305名个体进行了全基因组关联研究，并结合已发表的汇总统计数据进行了荟萃分析，得出了59,957名受试者的总样本量。我们确定了25个新的基因座，其中3个包含整合素基因，这些基因编码被确定为炎症性肠病重要治疗靶点的途径中的蛋白质。相关的变异与其中两个基因(ITGA4、ITGB8)和先前涉及的基因(ITGAL、ICAM1)对免疫刺激的表达变化相关。在所有四种情况下，表达增加的等位基因也会增加疾病风险。我们还发现了初级免疫缺陷基因PLCG2和炎症负调控因子SLAMF8中可能存在的原因错义变体。我们的结果表明，新的共同变异关联继续识别与治疗目标识别和优先排序相关的基因。
Genetic association studies have identified 215 risk loci for inflammatory bowel disease, which have revealed fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new loci, three of which contain integrin genes that encode proteins in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at previously implicated loci (ITGAL, ICAM1). In all four cases, the expression increasing allele also increases disease risk. We also identified likely causal missense variants in the primary immune deficiency gene PLCG2 and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes relevant to therapeutic target identification and prioritization.