Novel HLA-DP region susceptibility loci associated with severe acute GvHD
Novel HLA-DP region susceptibility loci associated with severe acute GvHD
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DOI：
10.1038/bmt.2016.210
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发表时间：
2017-01-01
影响因子：
4.8
通讯作者：
Ferrell, R. E.
中科院分区：
文献类型：
--
作者：
Goyal, R. K.;Lee, S. J.;Ferrell, R. E.
尽管 HLA 等位基因匹配，显着的急性 GvHD 仍然是成功的无关供体 BMT 的主要障碍。我们进行了全基因组关联研究 (GWAS)，以确定与急性 GvHD 风险相关的受体和供体基因。采用病例对照设计（III-IV级与无急性GvHD）和汇总GWA方法来研究患有血液恶性肿瘤的欧美受者，他们接受了来自HLA-A、-B、-C、-DRB1、-DQB1等位基因水平（10/10）匹配的无关供体的清髓性条件非T细胞耗尽的首次移植。 DNA 样品分为三个池，并使用 Affymetrix 全基因组 SNP 阵列 6.0 进行三次重复测试。我们在受体基因组的 HLA-DP 区域中发现了三个与 III-IV 急性 GvHD 相关的新易感位点（rs9277378，P=1.58E-09；rs9277542，P=1.548E-06 和 rs9277341，P=7.718E-05）。在这三个单核苷酸多态性（SNP）中，rs9277378和rs9277542位于HLA-DPB1基因的非编码区，并且这两个与另外两个已发表的与急性GvHD相关的SNP（rs2281389和rs9277535）存在强连锁不平衡。还发现了 18 个其他受者 SNP 和 3 个具有高显着性（8E-07 或更低）的供体 SNP。我们的报告提供了新的数据，显示 HLA-DP 区域遗传标记的临床意义超出了 DPB1 等位基因的结构匹配范围。
Despite HLA allele matching, significant acute GvHD remains a major barrier to successful unrelated donor BMT. We conducted a genome-wide association study (GWAS) to identify recipient and donor genes associated with the risk of acute GvHD. A case control design (grade III -IV versus no acute GvHD) and pooled GWA approach was used to study European-American recipients with hematological malignancies who received myeloablative conditioning non-T-cell-depleted first transplantation from HLA-A, -B, -C, -DRB1, -DQB1 allele level (10/10) matched unrelated donors. DNA samples were divided into three pools and tested in triplicate using the Affymetrix Genome-wide SNP Array 6.0. We identified three novel susceptibility loci in the HLA-DP region of recipient genomes that were associated with III-IV acute GvHD (rs9277378, P=1.58E-09; rs9277542, P=1.548E-06 and rs9277341, P=7.718E-05). Of these three single nucleotide polymorphisms (SNPs), rs9277378 and rs9277542 are located in non-coding regions of the HLA-DPB1 gene and the two are in strong linkage disequilibrium with two other published SNPs associated with acute GvHD, rs2281389 and rs9277535. Eighteen other recipient SNPs and 3 donor SNPs with a high level of significance (8E-07 or lower) were found. Our report contributes to emerging data showing clinical significance of the HLA-DP region genetic markers beyond structural matching of DPB1 alleles.