Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage
Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage
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DOI：
10.1093/humrep/den011
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发表时间：
2008-04-01
影响因子：
6.1
通讯作者：
Moffett, A.
中科院分区：
文献类型：
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作者：
Hiby, S. E.;Regan, L.;Moffett, A.
背景：胎盘部位的自然杀伤细胞(NK细胞)表达杀伤细胞免疫球蛋白样受体(KIR)，可与滋养层细胞上的人类白细胞抗原(HL A)-C分子结合。这两个基因系统都是多态的，在先兆子痫中已显示出特定的母体KIR/胎儿HLA-C基因类型的关联。先兆子痫和复发性流产(RM)与胎盘缺陷的发病机制相同，因此我们现在有RM的基因分型夫妇。方法和结果：从有3次或3次以上自然流产史夫妇的男性(n=67)和女性(n=95)配偶中提取DNA，采用序列特异性引物方法(SSP)进行人类白细胞抗原-C组和11个KIR基因分型。与产妇对照人群相比，父母双方的HLAC2组的频率增加(仅在男性伴侣中达到显著水平，P=0.018)。男性伴侣的KIR基因频率与对照组相似，但女性的KIR AA单倍型频率较高，缺乏激活的KIR。尤其是HLAC2组的激活KIR(KIR2DS1)在这些女性中显著降低(P=0.00035，优势比2.63，可信区间1.54~4.49)。结论：这是第一次发现男性遗传因素导致风湿性红斑狼疮。这些发现支持这样一种观点，即成功的胎盘形成依赖于NK细胞对滋养层细胞反应的抑制和激活之间的正确平衡。
BACKGROUND: The natural killer (NK) cells at the site of placentation express killer-cell immunoglobulin-like receptors (KIR) that can bind to human leukocyte antigen (HLA)-C molecules on trophoblast cells. Both these gene systems are polymorphic and an association of particular maternal KIR/fetal HLA-C genotypes has been shown in pre-eclampsia. Pre-eclampsia and recurrent miscarriage (RM) share the pathogenesis of defective placentation and therefore we have now genotyped couples with RM. METHODS AND RESULTS: DNA was obtained from the male (n = 67) and female (n = 95) partners of couples with three or more spontaneous miscarriages and genotyped for HLA-C groups and 11 KIR genes using the PCR-sequence-specific primer method (SSP). The frequency of the HLA-C2 group was increased in both parents (reaching significance only in the male partners, P = 0.018) compared with a parous control population. The KIR gene frequencies of the male partners were similar to controls, but the women had a high frequency of KIR AA haplotypes that lack activating KIR. In particular, the activating KIR for HLA-C2 groups (KIR2DS1) was significantly lower in these women (P = 0.00035, odds ratio 2.63, confidence interval 1.54-4.49). CONCLUSIONS: This is the first report to identify a genetic male factor that confers risk in RM. These findings support the idea that successful placentation depends on the correct balance of NK cell inhibition and activation in response to trophoblast.