Department of Oncology and Haematology, Roskilde Hospital, Copenhagen University, DK-4000, Roskilde, Denmark.
Ann Hematol. 2011 Jun;90(6):675-84. doi: 10.1007/s00277-010-1105-z. Epub 2010 Nov 3.
The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF-κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3–6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none of the haplotypes were more strongly associated to TTF or OS than the two strongly linked SNPs, RAI-intron1-1 (rs4572514) and CD3EAP G-21A (rs967591). The association of RAI-intron1-1 and CD3EAP G-21A with TTF was independent of NFKB1-94 ins/del, but homozygous ins-allele carriers which were also variant allele carriers of RAI-intron1-1 or CD3EAP G-21A had the longest OS. Among patients treated with INF-α or thalidomide, no effect was seen in relation to genotype. Our results indicate that polymorphism in RAI and CD3EAP are associated with outcome of myeloma patients treated with HDT. Combination analyses with the functional polymorphism in NFKB1 suggest that a possibly functional effect of RAI or CD3EAP could be related to NF-κB availability.
RAI 基因最初被描述为核因子 κB（NF-κB）RelA/p65 亚基的抑制剂。在这里，我们分析了基因 RAI 和 CD3EAP 的遗传变异与 348 例接受高剂量治疗（HDT）、146 例接受干扰素-α（INF-α）作为维持治疗、177 例接受沙利度胺和 74 例硼替佐米治疗的多发性骨髓瘤患者的结果之间的关系复发，并确定 CD3EAP 和 RAI 多态性的影响是否受 NFКB1 功能多态性的调节。通过连锁不平衡作图，我们发现 CD3EAP 中跨越 RAI-intron1-1 到 RAI intron1-3 区域和 exon1 到 exon3-6 区域的 19q13.3 亚区的几个多态性的变异等位基因与治疗失败时间（TTF；p=0.003）和总生存（OS；p=0.02）延长相关。单体型分析显示，没有一个单体型与 TTF 或 OS 的相关性强于两个紧密连锁的 SNP，即 RAI-intron1-1（rs4572514）和 CD3EAP G-21A（rs967591）。RAI-intron1-1 和 CD3EAP G-21A 与 TTF 的关联独立于 NFKB1-94 ins/del，但也是 RAI-intron1-1 或 CD3EAP G-21A 的变异等位基因携带者的纯合 ins 等位基因携带者具有最长的 OS。在接受 INF-α或沙利度胺治疗的患者中，基因型与疗效无关。与 NFKB1 中功能性多态性的组合分析表明，RAI 或 CD3EAP 的可能功能效应可能与 NF-κB 的可用性有关。
