Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance
Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance
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DOI：
10.1158/0008-5472.can-05-2776
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Nakachi, K
中科院分区：
文献类型：
--
作者：
Hayashi, T;Imai, K;Nakachi, K
我们以前已经表明，外周血淋巴细胞的天然细胞毒活性与癌症的发展呈负相关的前瞻性队列研究的基础上。细胞毒活性的遗传部分需要澄清，确定个体免疫遗传易感癌症。设计了一项队列成员的病例对照研究：102例外周淋巴细胞DNA可用的癌症病例和3个对照组，每组由204例受试者组成，每个三分位水平的细胞毒活性。我们首先：在染色体12 p上的自然杀伤复合物基因区域的单核苷酸多态性方面，比较了具有高和低细胞毒活性的两个对照组，鉴定了与活性相关的单倍型等位基因。接下来，评估这些单倍型的癌症风险。我们发现了两个单倍型区块，每个区块产生两个主要的单倍型等位基因：低活性相关的LNK 1（高活动组和低活动组的频率分别为0.478和0.615; P < 0.00008）和高活动相关的HNK 1（0.480和0.348; P < 0.0001）、LNK 2（0.711和0.821; P < 0.0002）和HNK 2（0.272和0.174; P < 0.0008）。这些NKG 2D单倍型等位基因在病例组（LNK 1为0.632，HNK 1为0.333）和对照组（LNK 1为0.554，HNK 1为0.406）之间显示出显著差异。与LNK 1/LNK 1相比，HNK 1/HNK 1的癌症风险降低（比值比，0.471; 95%置信区间，0.233-0.952）。遗传上倾向于具有低或高天然细胞毒活性的个体可以部分地由NKG 2D单体型决定，这反过来揭示了癌症发展风险的增加或降低。
We have previously shown that natural cytotoxic activity of peripheral blood lymphocytes was inversely related to cancer development based on a prospective cohort study. The genetic fraction of cytotoxic activity needs to be clarified, identifying individuals immunogenetically susceptible to cancer. A casecontrol study within the cohort members was designed: 102 cancer cases with peripheral lymphocyte DNA available and three control groups, each of which consisted of 204 subjects with each tertile level of cytotoxic activity. We first: compared two control groups with high and low cytotoxic activity in terms of the single nucleotide polymorphisms in the natural killer complex gene region on chromosome 12p, identifying the haplotype alleles that were associated with the activity. Next, cancer risks were assessed for these haplotypes. We found two haplotype blocks, each of which generated two major haplotype alleles: low-activity-related LNK1 (frequency 0.478 and 0.615 in groups with high and low activity, respectively; P < 0.00008) and high-activity-related HNK1 (0.480 and 0.348; P < 0.0001), LNK2 (0.711 and 0.821; P < 0.0002), and HNK2 (0.272 and 0.174; P < 0.0008). These NKG2D haplotype alleles showed a significant difference between cases (0.632 for LNK1 and 0.333 for HNK1) and controls (0.554 for LNK1 and 0.406 for HNK1). The haplotype HNK1/HNK1 revealed a decreased risk of cancer (odds ratio, 0.471; 95% confidence interval, 0.233-0.952) compared with LNK1/LNK1. Individuals who are genetically predisposed to have low or high natural cytotoxic activity can in part lie determined by NKG2D haplotyping, which in turn reveals an increased or decreased risk of cancer developement.