García-Lozano José-Raúl, Torres-Agrela Belén, Montes-Cano Marco-Antonio, Ortiz-Fernández Lourdes, Conde-Jaldón Marta, Teruel María, García Alicia, Núñez-Roldán Antonio, Martín Javier, González-Escribano María-Francisca
Arthritis Res Ther. 2013 Jan 15;15(1):R11. doi: 10.1186/ar4141.
AIRE is a transcriptional regulator playing a functional role in thymocyte education and negative selection by controlling the expression of peripheral antigens in the thymus. Recently, the AIRE gene was identified as a genetic risk factor for rheumatoid arthritis (RA) in genome wide association (GWA) studies performed in the Japanese population. According to the available data this association is restricted to the Asian population. However, different facts could influence the lack of association in Caucasian populations. The aim of this study was to further investigate the possible role of the AIRE gene in susceptibility to RA in a Caucasian population.
A total of 472 Spanish Caucasian RA patients and 475 ethnically matched controls were included in the study. Three single-nucleotide polymorphisms (SNPs) (rs2776377, rs878081 and rs1055311) with a minor allele frequency>0.05 in the Caucasian population which were not included in the high-throughput platforms used in the GWA studies performed in susceptibility to RA, and two SNPs (rs2075876 and rs1800520) associated with RA in the Japanese population, were selected and genotyped using TaqMan assays.
No significant differences in the distribution of the alleles of rs2776377, rs2075876, rs1055311 and rs1800520 SNPs between RA patients and controls were observed. Nevertheless, the frequency of the C allele of rs878081 was significantly higher among RA patients (80.5% vs. 74.6% in the control group, pc=0.012, OR=1.41, 95%CI 1.13-1.75). Regarding the distribution of the rs878081 genotypes, a higher frequency of CC homozygous individuals was found in the RA patient group (65.56% vs. 56.47% in the control group, pc=0.013, OR=1.47, 95%CI 1.12-1.93). The in silico analysis predicted lower affinity to the binding-site of a motif of the transcription NF-κB family and lower transcription levels of AIRE gene for the rs878081C risk variant
Our findings suggest that the AIRE gene is associated with susceptibility to RA in the Spanish population. Probably, this association has not been detected in the European population in the GWA studies because the earliest high-throughput platforms did not include SNP suitable markers (e.g. rs878081).
自身免疫调节因子（AIRE）是一种转录调节因子，通过控制胸腺中外周抗原的表达，在胸腺细胞发育和阴性选择中发挥功能作用。最近，在针对日本人群进行的全基因组关联（GWA）研究中，AIRE基因被确定为类风湿关节炎（RA）的遗传风险因素。根据现有数据，这种关联仅限于亚洲人群。然而，不同因素可能导致在高加索人群中未发现这种关联。本研究的目的是进一步调查AIRE基因在高加索人群对RA易感性中的可能作用。
本研究共纳入472名西班牙高加索RA患者和475名种族匹配的对照。选择了3个单核苷酸多态性（SNP）（rs2776377、rs878081和rs1055311），其在高加索人群中的次要等位基因频率>0.05，且未包含在针对RA易感性进行的GWA研究中使用的高通量平台中，以及2个在日本人群中与RA相关的SNP（rs2075876和rs1800520），采用TaqMan分析进行基因分型。
在RA患者和对照之间，未观察到rs2776377、rs2075876、rs1055311和rs1800520 SNP等位基因分布的显著差异。然而，rs878081的C等位基因频率在RA患者中显著更高（80.5%对对照组的74.6%，pc = 0.012，OR = 1.41，95%CI 1.13 - 1.75）。关于rs878081基因型的分布，在RA患者组中发现CC纯合个体的频率更高（65.56%对对照组的56.47%，pc = 0.013，OR = 1.47，95%CI 1.12 - 1.93）。计算机模拟分析预测，rs878081C风险变异对转录因子NF - κB家族基序结合位点的亲和力较低，且AIRE基因的转录水平较低。
我们的研究结果表明，AIRE基因与西班牙人群对RA的易感性相关。可能在GWA研究的欧洲人群中未检测到这种关联，因为最早的高通量平台未包括合适的SNP标记（如rs878081）。
