Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.
Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.
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DOI：
10.1038/ng.3786
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发表时间：
2017-03
期刊：
影响因子：
30.8
通讯作者：
Remmers EF
中科院分区：
文献类型：
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作者：
Takeuchi M;Mizuki N;Meguro A;Ombrello MJ;Kirino Y;Satorius C;Le J;Blake M;Erer B;Kawagoe T;Ustek D;Tugal-Tutkun I;Seyahi E;Ozyazgan Y;Sousa I;Davatchi F;Francisco V;Shahram F;Abdollahi BS;Nadji A;Shafiee NM;Ghaderibarmi F;Ohno S;Ueda A;Ishigatsubo Y;Gadina M;Oliveira SA;Gül A;Kastner DL;Remmers EF
我们分析了1900例土耳其behet病病例和1779例用免疫芯片进行基因分型的对照。最显著相关的单核苷酸多态性（SNP）为rs1050502，这是HLA-B*51的标签SNP。在土耳其的发现集中，我们发现了三个新的基因座，IL1A-IL1B， IRF8和CEBPB-PTPN1，通过直接基因分型具有全基因组意义（P<5×10−8），通过代入确定了ido - egr2。通过对969例伊朗病例和826例对照进行基因分型，复制了ido - egr2、IRF8和CEBPB-PTPN1。608例日本病例和737例对照的输入数据重复了ido - egr2和IRF8，荟萃分析还确定了RIPK2和LACC1。IL1A-IL1B位点的主要标记rs4402765的疾病相关等位基因与白细胞介素-1α的减少和白细胞介素-1β的增加有关。两个祖先特异性FUT2 snp的ABO非分泌基因型显示出很强的疾病相关性（P=5.89×10−15）。我们的研究结果扩展了克罗恩病和麻风病的共同易感基因，并暗示粘膜因素和对微生物暴露的先天免疫反应与behet病易感性有关。
We analyzed 1,900 Turkish Behçet’s disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated single nucleotide polymorphism (SNP) was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three novel loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P<5×10−8) by direct genotyping, and ADO-EGR2 by imputation. ADO-EGR2, IRF8, and CEBPB-PTPN1 replicated by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls replicated ADO-EGR2 and IRF8 and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker of the IL1A-IL1B locus, was associated with both decreased interleukin-1α and increased interleukin-1β production. ABO non-secretor genotypes of two ancestry-specific FUT2 SNPs showed strong disease association (P=5.89×10−15). Our findings extend shared susceptibility genes with Crohn’s disease and leprosy, and implicate mucosal factors and the innate immune response to microbial exposure in Behçet’s disease susceptibility.