Seripa Davide, Matera Maria G, Dal Forno Gloria, Gravina Carolina, Masullo Carlo, Daniele Antonio, Binetti Giuliano, Bonvicini Cristian, Squitti Rosanna, Palermo Mark T, Davis Daron G, Antuono P, Wekstein David R, Dobrina Aldo, Gennarelli Massimo, Fazio Vito M
Laboratory of Gene Therapy, I.R.C.C.S. Casa Sollievo della Sofferenza, Padre Pio da Pietrelcina Foundation, San Giovanni Rotondo, FG, Italy.
Neurobiol Aging. 2005 Apr;26(4):455-64. doi: 10.1016/j.neurobiolaging.2004.04.001.
Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.
阿尔茨海默病（AD）风险增加与白细胞介素-1（IL-1）基因簇多态性有关，尤其是与IL-1α-889 T/T基因型有关。然而，这种关联仍不明确，需要进一步研究。为了阐明这些多态性在AD复杂发病机制中的作用，我们分别检测了IL-1α基因-889位点和IL-1β基因-551位点两个C→T单核苷酸多态性（SNP）以及IL-1受体拮抗剂（IL-1Ra）基因内含子2 86 bp可变数目串联重复序列（VNTR）多态性的基因型和单倍型频率。分析在来自意大利和美国的两个遗传和诊断上不同的散发性AD组中进行。在意大利组中，发现IL-1α-889 T/T基因型与AD之间存在显著关联（比值比[OR]=3.022，95%可信区间[CI]：1.001 - 9.119），而在美国组中未发现差异。结果还与之前发表的分析AD中相同IL-1多态性的研究进行了比较。在两组中，对估计单倍型的分析表明，携带IL-1β-511 C等位基因的AD患者和对照也更频繁地携带IL-1Ra 1等位基因（单倍型-C-1）。两个-C-1单倍型（C-C-1加T-C-1）的总频率约为八个估计单倍型总频率的一半。意大利组和美国组中这两个位点之间显著的连锁不平衡证实了这一点。在意大利组中还发现T-C-2单倍型与疾病有弱关联（OR=1.648，95%CI：1.519 - 1.788），而在美国组中未发现差异。尽管我们和其他关于不同白种人和非白种人AD样本的已发表数据显示IL-1α-889、IL-1β-511和IL-1Ra VNTR基因多态性频率存在很大异质性，但我们证实IL-1α-889 T/T基因型作为散发性AD的危险因素的作用，并表明在意大利组和美国组中IL-β C和IL-1Ra 1等位基因之间存在等位基因关联，这两个位点之间显著水平的连锁不平衡证实了这一点。
