Association of killer cell immunoglobulin-like receptor genes with Hodgkin's lymphoma in a familial study.
Association of killer cell immunoglobulin-like receptor genes with Hodgkin's lymphoma in a familial study.
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DOI：
10.1371/journal.pone.0000406
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发表时间：
2007-05-02
期刊：
影响因子：
3.7
通讯作者：
Abel L
中科院分区：
文献类型：
--
作者：
Besson C;Roetynck S;Williams F;Orsi L;Amiel C;Lependeven C;Antoni G;Hermine O;Brice P;Ferme C;Carde P;Canioni D;Brière J;Raphael M;Nicolas JC;Clavel J;Middleton D;Vivier E;Abel L
爱泼斯坦-巴尔病毒(Epstein-Barr Virus，EBV)是青年常见的霍奇金淋巴瘤(Hodgkin‘s ymoma，HL)的主要环境因素。自然杀伤(NK)细胞是针对病毒的先天免疫反应的关键分子。NK细胞功能的调节包括激活和抑制杀伤细胞免疫球蛋白样受体(KIRS)，KIR在NK细胞上以可变数量表达。在病例/对照研究中，各种病毒和病毒相关的恶性疾病与某些KIR基因的存在/缺失有关。我们在一项基于家族的关联研究中研究了KIR簇在HL中的作用。我们包括90个家庭，90个HL指数病例(年龄16-35岁)和255个一级亲属(父母和兄弟姐妹)。我们开发了一种从标准KIR基因内容中重建每个KIR基因座的完整基因类型信息(基因拷贝数)的程序。在收集到的90个家系中，84个家系信息丰富，适合进一步分析。然后用特定的以家庭为基础的分析方法对这84个家庭进行了关联研究。有5个KIR基因处于强连锁不平衡状态，与HL显著相关。改进的单倍型分析表明，这种关联得到了KIR3DS1和/或KIR2DS1的显性保护作用的支持，这两个基因都是激活受体。KIR3DS1或KIR2DS1至少有一个拷贝的受试者与没有这两个基因的受试者相比，发生HL的优势比分别为0.44[95%可信区间0.23~0.85]和0.42[0.21~0.85]。在一项对68例HL患者(年龄18-71岁)进行的临时性复制病例/对照研究中，没有发现显著的相关性。在家族性研究中，在血液或肿瘤细胞中检测到EBV的HL患者中，KIR3DS1/KIR2DS1的保护作用往往更强。这项工作基于KIR簇的完整基因信息，为基于家族的关联研究定义了一个模板，并提供了第一个证据，表明激活KIR在HL中可以起到保护作用。
Epstein-Barr virus (EBV) is the major environmental factor associated with Hodgkin's lymphoma (HL), a common lymphoma in young adults. Natural killer (NK) cells are key actors of the innate immune response against viruses. The regulation of NK cell function involves activating and inhibitory Killer cell Immunoglobulin-like receptors (KIRs), which are expressed in variable numbers on NK cells. Various viral and virus-related malignant disorders have been associated with the presence/absence of certain KIR genes in case/control studies. We investigated the role of the KIR cluster in HL in a family-based association study. We included 90 families with 90 HL index cases (age 16–35 years) and 255 first-degree relatives (parents and siblings). We developed a procedure for reconstructing full genotypic information (number of gene copies) at each KIR locus from the standard KIR gene content. Out of the 90 collected families, 84 were informative and suitable for further analysis. An association study was then carried out with specific family-based analysis methods on these 84 families. Five KIR genes in strong linkage disequilibrium were found significantly associated with HL. Refined haplotype analysis showed that the association was supported by a dominant protective effect of KIR3DS1 and/or KIR2DS1, both of which are activating receptors. The odds ratios for developing HL in subjects with at least one copy of KIR3DS1 or KIR2DS1 with respect to subjects with neither of these genes were 0.44[95% confidence interval 0.23–0.85] and 0.42[0.21–0.85], respectively. No significant association was found in a tentative replication case/control study of 68 HL cases (age 18–71 years). In the familial study, the protective effect of KIR3DS1/KIR2DS1 tended to be stronger in HL patients with detectable EBV in blood or tumour cells. This work defines a template for family-based association studies based on full genotypic information for the KIR cluster, and provides the first evidence that activating KIRs can have a protective role in HL.
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