Sillé F C M, Conde L, Zhang J, Akers N K, Sanchez S, Maltbaek J, Riby J E, Smith M T, Skibola C F
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.
Department of Epidemiology, Comprehensive Cancer Center, University of Alabama, Birmingham, AL, USA.
Genes Immun. 2014 Mar;15(2):133-6. doi: 10.1038/gene.2013.64. Epub 2013 Dec 5.
Multiple follicular lymphoma (FL) susceptibility single-nucleotide polymorphisms in the human leukocyte antigen (HLA) class I and II regions have been identified, including rs6457327, rs3117222, rs2647012, rs10484561, rs9268853 and rs2621416. Here we validated previous expression quantitative trait loci results with real-time reverse transcription quantitative PCR and investigated protein expression in B-lymphoblastoid cell lines and primary dendritic cells using flow cytometry, cell-based enzyme-linked immunosorbent assay and western blotting. We confirmed that FL-protective rs2647012-linked variants, in high linkage disequilibrium with the extended haplotype DRB115:01-DQA101:02-DQB1*06:02, correlate with increased HLA-DQB1 expression. This association remained significant at the protein level and was reproducible across different cell types. We also found that differences in HLA-DQB1 expression were not related to changes in activation markers or class II, major histocompatibility complex, transactivator expression, suggesting the role of an alternative regulatory mechanism. However, functional analysis using RegulomeDB did not reveal any relevant regulatory candidates. Future studies should focus on the clinical relevance of increased HLA-DQB1 protein expression facilitating tumor cell removal through increased immune surveillance.
已在人类白细胞抗原（HLA）I类和II类区域中鉴定出多种滤泡性淋巴瘤（FL）易感性单核苷酸多态性，包括rs6457327、rs3117222、rs2647012、rs10484561、rs9268853和rs2621416。在此，我们通过实时逆转录定量PCR验证了先前的表达数量性状位点结果，并使用流式细胞术、基于细胞的酶联免疫吸附测定和蛋白质印迹法研究了B淋巴母细胞系和原代树突状细胞中的蛋白质表达。我们证实，与扩展单倍型DRB115:01-DQA101:02-DQB1*06:02处于高度连锁不平衡状态的FL保护性rs2647012相关变体与HLA-DQB1表达增加相关。这种关联在蛋白质水平上仍然显著，并且在不同细胞类型中具有可重复性。我们还发现，HLA-DQB1表达的差异与激活标志物或II类主要组织相容性复合体反式激活因子表达的变化无关，这表明存在一种替代调节机制。然而，使用RegulomeDB进行的功能分析未发现任何相关的调节候选物。未来的研究应关注HLA-DQB1蛋白表达增加通过增强免疫监视促进肿瘤细胞清除的临床相关性。
