Feuk L, Prince J A, Breen G, Emahazion T, Carothers A, St Clair D, Brookes A J
Center for Genomics Research, Karolinska Institute, Stockholm, Sweden.
Hum Genet. 2000 Oct;107(4):391-6. doi: 10.1007/s004390000383.
The TNFRSF6 gene encodes FAS, a cell-surface receptor involved in apoptosis initiation. Elevated levels of FAS have been reported in the brains of Alzheimer's disease (AD) patients. We have tested a G/A polymorphism at position -670 in the TNFRSF6 gene for association with non-familial, early onset Alzheimer's disease (EOAD) by using dynamic allele-specific hybridization. In an initial set of Scottish EOAD cases (n=78) and controls (n=152), we found that, for individuals carrying one or two APOE4 alleles, the homozygous GG-genotype was enriched in the patients (26.7% versus 10.9% in controls). A second study was conducted on an independent set of Scottish individuals (87 EOAD, 358 controls). In this material, the TNFRSF6 GG-genotype frequency was elevated in patients regardless of APOE4 status (28.7% versus 15.1%) and was even more enriched in APOE4 carriers (35.9% versus 15.3%). A combination of the two sample sets (165 cases, 510 controls) gave a significant disease association for the TNFRSF6 GG-genotype that was irrespective of APOE4 (P=0.0020) and that was almost completely attributable to the enrichment present within the set of APOE4 carriers (P=0.0016). This represents an odds ratio of 8.71 for GG-homozygotes carrying at least one APOE4 allele compared with other TNFRSF6 genotypes in APOE4 non-carriers. The TNFRSF6 variation was further explored in Scottish late-onset Alzheimer's disease (n=159) but no associations were found. These results imply that TNFRSF6, in interaction with APOE4, is a genetic risk factor for sporadic EOAD. Hence, the AD risk contributed by APOE4 could be mechanistically related to a pathway in common with FAS-mediated apoptosis.
肿瘤坏死因子受体超家族6（TNFRSF6）基因编码FAS，这是一种参与启动细胞凋亡的细胞表面受体。据报道，阿尔茨海默病（AD）患者大脑中FAS水平升高。我们通过动态等位基因特异性杂交检测了TNFRSF6基因-670位的G/A多态性与非家族性早发性阿尔茨海默病（EOAD）的相关性。在最初一组苏格兰EOAD病例（n = 78）和对照（n = 152）中，我们发现，对于携带一个或两个APOE4等位基因的个体，纯合GG基因型在患者中更为富集（26.7%，而对照中为10.9%）。对另一组独立的苏格兰个体（87例EOAD，358例对照）进行了第二项研究。在该样本中，无论APOE4状态如何，患者中TNFRSF6 GG基因型频率均升高（28.7%对15.1%），在APOE4携带者中更为富集（35.9%对15.3%）。将两个样本集合并（165例病例，510例对照）后，TNFRSF6 GG基因型与疾病存在显著关联，且与APOE4无关（P = 0.0020），几乎完全归因于APOE4携带者组中的富集现象（P = 0.0016）。与APOE4非携带者中的其他TNFRSF6基因型相比，携带至少一个APOE4等位基因的GG纯合子的优势比为8.71。我们在苏格兰晚发性阿尔茨海默病患者（n = 159）中进一步研究了TNFRSF6变异，但未发现关联。这些结果表明，TNFRSF6与APOE4相互作用时，是散发性EOAD的一个遗传风险因素。因此，APOE4导致的AD风险可能在机制上与FAS介导的细胞凋亡共同通路有关。
