Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.
Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.
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DOI：
10.1053/j.gastro.2015.07.065
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发表时间：
2015-11
期刊：
影响因子：
29.4
通讯作者：
Kugathasan S
中科院分区：
文献类型：
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作者：
Huang C;Haritunians T;Okou DT;Cutler DJ;Zwick ME;Taylor KD;Datta LW;Maranville JC;Liu Z;Ellis S;Chopra P;Alexander JS;Baldassano RN;Cross RK;Dassopoulos T;Dhere TA;Duerr RH;Hanson JS;Hou JK;Hussain SZ;Isaacs KL;Kachelries KE;Kader H;Kappelman MD;Katz J;Kellermayer R;Kirschner BS;Kuemmerle JF;Kumar A;Kwon JH;Lazarev M;Mannon P;Moulton DE;Osuntokun BO;Patel A;Rioux JD;Rotter JI;Saeed S;Scherl EJ;Silverberg MS;Silverman A;Targan SR;Valentine JF;Wang MH;Simpson CL;Bridges SL;Kimberly RP;Rich SS;Cho JH;Rienzo AD;Kao LWH;McGovern DPB;Brant SR;Kugathasan S
炎症性肠病(IBD)在非裔美国人(AAs)中具有家族聚集性，但对其分子遗传易感性知之甚少。利用免疫芯片基因分型阵列进行的图谱研究将高加索人IBD的易感基因座数量扩大到163个，但这163个基因座和欧洲混合体对AAS中IBD风险的贡献尚不清楚。我们使用免疫芯片进行了一项基因图谱研究，以确定高加索人的IBD易感基因是否也影响AA的风险，并确定新的相关基因座。我们从美国34个IBD中心招募了有IBD的AA和没有IBD的AA(对照组)；其他的对照来自其他4个免疫芯片研究。对1088例克罗恩病(CD)、361例溃疡性结肠炎(UC)、62例IBD类型不明(IBDU)患者和1797例正常对照进行了关联和混合基因座定位，分析了130,241个常染色体单核苷酸多态(SNPs)。UC与HLArs9271366(P=7.5e-6)、CD与5p13.1 rs4286721(P=3.0e-6)、IBD与KAT2Ars730086(P=2.3e-6)的相关性最强。此外，还观察到CD和IBD与STAT5A和STAT3中非洲特有的SNP之间的关联，IBD与IL23R、IL12B和C2开放阅读框架43中的SNP之间的关联，以及UC与HDAC11和LINC00994附近的SNPs之间的关联。后3个基因座以前未发现与IBD相关，但需要复制。在AAS(P<；3.1e-4)中，在NOD2、IL23R、5p15.3和IKZF3处复制了已建立的高加索人关联。17q12-17q21.31(IZKF3至STAT3)、10q11.23-10q21.2、15q22.2-15q23和16p12.2-16p12.1存在显著的混合(P<；3.9e-4)。网络分析显示，编码JAK-STAT、细胞因子和趋化因子信号通路成员以及参与麻疹发病机制的基因显著丰富(错误发现率为lt；1e-5)。在对3308例AA IBD病例和对照的遗传分析中，我们发现许多与高加索人IBD相关的变异也显示出与AA这些疾病相关的证据；我们发现了以前与IBD无关的基因座和变异的证据。在不同人群中决定IBD风险或保护措施的复杂遗传因素需要进一步研究。
Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the US; additional controls were collected from 4 other immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease (CD), 361 with ulcerative colitis (UC), 62 with IBD type-unknown (IBDU), and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. The strongest associations were observed between UC and HLA rs9271366 (P=7.5e–6), CD and 5p13.1 rs4286721 (P=3.0e–6), and IBD and KAT2A rs730086 (P=2.3e–6). Additional suggestive associations (P<4.2e-5) were observed between CD and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2 open reading frame 43; and between UC and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P<3.1e-4) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P<3.9e–4) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2–15q23, and 16p12.2–16p12.1. Network analyses showed significant enrichment (false discovery rate <1e–5) in genes that encode members of the JAK–STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we found evidence for loci and variants not previously associated with IBD. The complex genetic factors that determine risk for or protection from IBD in different populations require further study.